Abstract

Since its initial description as a Th2-cytokine antagonistic to interferon-alpha and granulocyte-macrophage colony-stimulating factor, many studies have shown various anti-inflammatory actions of interleukin-10 (IL-10), and its role in infection as a key regulator of innate immunity. Studies have shown that IL-10 induced in response to microorganisms and their products plays a central role in shaping pathogenesis. IL-10 appears to function as both sword and shield in the response to varied groups of microorganisms in its capacity to mediate protective immunity against some organisms but increase susceptibility to other infections. The nature of IL-10 as a pleiotropic modulator of host responses to microorganisms is explained, in part, by its potent and varied effects on different immune effector cells which influence antimicrobial activity. A new understanding of how microorganisms trigger IL-10 responses is emerging, along with recent discoveries of how IL-10 produced during disease might be harnessed for better protective or therapeutic strategies. In this review, we summarize studies from the past 5 years that have reported the induction of IL-10 by different classes of pathogenic microorganisms, including protozoa, nematodes, fungi, viruses and bacteria and discuss the impact of this induction on the persistence and/or clearance of microorganisms in the host.

Introduction: IL-10 in infection

Fulminating microbial infection involves severe tissue pathology that typically stems from excessive host signalling pro-inflammatory cascades such as those described by the so-called ‘cytokine-storm’ model (Bisno et al., 2003; Stanford et al., 2007; Schreiner & Liesenfeld, 2009). Excessive immune responses, which, in the case of bacterial pathogens are triggered by unique structures such as lipopolysaccharide (LPS) (Ianaro et al., 2009), can lead to organ-specific inflammation to such a degree that irreversible septic shock ensues (Latifi et al., 2002). Uncontrolled immunopathology influences the pathogenesis and progression of colitis during enteric infections (Kullberg et al., 2002), in the inflammation of infected airways (Demangel et al., 2002) and in disseminated intravascular coagulation leading to sepsis (van der Poll & Opal, 2008). Infection-induced inflammation and immunopathology resulting from it is often associated with deregulated haematopoiesis, and, in addition to cytokine ‘storms’ usually comprises abnormal proliferation of cells that mediate innate and adaptive immune responses such as natural killer (NK) cells, cytotoxic T lymphocytes (CTLs) and other lymphocyte subsets (Couper et al., 2008a, b; Moreira et al., 2008). Interleukin-10 (IL-10) is a central player that moderates these potentially excessive immune responses during infection (Mege et al., 2006).

Much of the current knowledge of IL-10 function in infection is derived from the investigations of immune defence mechanisms that function at first-contact, mucosal sites of colonization such as the gastrointestinal and respiratory tracts [as reviewed in (O'Garra et al., 2008)], and more recently, the urinary tract (Duell et al., 2012). In acute infections, high microbial loads that may develop on the surface of the mucosa often induce severe inflammatory responses but such responses are moderated by the balance between T Helper (Th)1 and Th2 effector mechanisms (Fiorentino et al., 1989). On the one hand, Th1 responses promote cell-mediated immunity (CMI) enabling phagocytosis, degranulation of cells such as neutrophils, and the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS) to kill invading pathogens (Couper et al., 2008a, b). In contrast, Th2 responses favour humoral immunity by promoting B lymphocyte clonal selection and production of pathogen-specific immunoglobulins (Ig) such as secretory IgA (sIgA) at the mucosa (Couper et al., 2008a, b). An inappropriate balance between Th1, Th2 and antigen (Ag)-specific responses thwarts effective antimicrobial responses and enables invading microorganisms to survive, which can lead to immunopathology caused by chronic inflammation and persistent infection (Fleming et al., 1999). Cytokines from both Th1 and Th2 responses are involved in intimate cross-regulation of homoeostasis and pathology, which has been described in various infection models that have dissected the balance between pro- and anti-inflammatory responses (O'Garra et al., 2004). In bacterial, parasitic, viral and fungal infections IL-10 functions as a moderator of these responses (Mege et al., 2006; Couper et al., 2008a, b) where it works to achieve balance between Th1 and Th2 responses within the dynamic host environment during infection. Recent reports of IL-10 in protozoan, fungal, nematode and viral, in addition to bacterial infections are outlined in Table 1. Thus, as an anti-inflammatory that inhibits the production of various pro-inflammatory factors (Moore et al., 2001), IL-10 can moderate infection-associated immunopathology linked with strong Th1 responses (Maloy et al., 2003). IL-10 also drives secretion of microorganism-specific IgA and B lymphocyte activation (Defrance et al., 1988, 1992; Fernandez-Botran et al., 1989; Moore et al., 1990; Rousset et al., 1991, 1992; Vieira et al., 1991).

Table 1

Recently discovered microbial triggers of IL-10 during infection

Type of microbe and pathogen Cellular or tissue source of IL-10 Species Year References 
Protozoa 
    Leishmania amazonensis Dendritic Cell 2007 Xin et al. (2007) 
    Leishmania braziliensis Monocyte; Macrophage 2010 Vargas-Inchaustegui et al. (2010) 
    Leishmania chagasi Macrophage; T Cell 2008 Ettinger & Wilson (2008) 
    Leishmania donovani Dermal Lesion 2011 Katara et al. (2011) 
    Leishmania guyanensis CD45RA(−) CD4(+)/CD8(+) T Cell 2007 Bourreau et al. (2007) 
    Leishmania major Dendritic Cell 2007 Xin et al. (2007) 
    Plasmodium spp. Plasma 2010 Han et al. (2010) 
    Schistosoma japonicum CD4(+) CD25(+) T Cell 2007 Yang et al. (2007) 
    Toxoplasma gondii Splenocyte 2010 Guiton et al. (2010) 
    Trypanosoma brucei Plasma 2010 Morrison et al. (2010) 
    Trypanosoma cruzi Splenocyte 2010 Rodrigues et al. (2010) 
Nematodes and fungi 
    Heligmosomoides polygyrus Monocyte; T Cell H; M 2007 Setiawan et al. (2007), Rocha-Ramirez et al. (2008) 
    Paracoccidioides brasiliensis Monocyte; Dendritic Cell H; M 2007 Ferreira et al. (2007), Kurokawa et al. (2007) 
    Paracoccidioides brasiliensis Vaccine Lung Extracts 2009 Braga et al. (2009) 
Viruses 
    Chikungunya Virus Plasma; Serum 2011 Kelvin et al. (2011), Wauquier et al. (2011) 
    Crimean-Congo Haemorrhagic Fever Virus Plasma 2010 Saksida et al. (2010) 
    Cytomegalovirus Plasma; Serum 2010 Waters et al. (2010) 
    Epstein–Barr Virus Nasopharyngeal Carcinoma; Plasma 2007–2009 Ogino et al. (2007), Wingate et al. (2009) 
    Herpesvirus-6 Cerebrospinal Fluid 2010 Kawabe et al. (2010) 
    Human Immunodeficiency virus Cervicovaginal Lavage; Plasma 2008–2009 Bebell et al. (2008), Barqasho et al. (2009) 
    Human Papilloma Virus Dendritic Cell 2007 De Witte et al. (2007) 
    Tacaribe Virus Monocyte; Macrophage 2011 Groseth et al. (2011) 
Bacteria 
    Bacteroides fragilis Serum 2011 Cohen-Poradosu et al. (2011) 
    Borrelia burgdorferi Macrophage H; M 2008–2009 Lazarus et al. (2008), Strle et al. (2009) 
    Borrelia turicatae Plasma; Brain and Heart Tissue 2007 Gelderblom et al. (2007) 
    Burkholderia pseudomallei Splenocyte; Hepatocyte; Dendritic Cell 2000–2011 Ulett et al. (2000, 2005), Williams et al. (2011) 
    Chlamydia pneumoniae Monocyte; Macrophage; T Cell; Gingival Fibroblast M; H 2008–2011 Mamata et al. (2007), Rizzo et al. (2008), Bermudex-Fajardo et al. (2011) 
    Chlamydia trachomatis Cervical Lymphocyte; Conjunctival Mucosa; Macrophage 2007–2011 Vats et al. (2007), Skwor et al. (2008), Agrawal et al. (2009a, b), Azenabor et al. (2011) 
    Chlamydia muridarum Plasmacytoid Dendritic Cell 2009 Moniz et al. (2009) 
    Escherichia coli Bladder; Monocyte; Urine Stool M; H 2010–2011 Jongyota et al. (2008), Long et al. (2010), Duell et al. (2012) 
    Helicobacter pylori Macrophage; Plasma H; M 2007–2008 Obonyo et al. (2007), Kayhan et al. (2008) 
    Legionella pneumophila Macrophage; Epithelial Cell 2011 McCoy-Simandle et al. (2011) 
    Leptospira biflexa Monocyte H; M 2008 Jongyota et al. (2008) 
    Leptospira interrogans Monocyte; Spleenocyte; Whole Blood H; M; Ha 2008–2011 Jongyota et al. (2008), Vernel-Pauillac & Goarant (2010) 
    Mycobacterium avium Monocyte 2008–2011 Souza et al. (2008), Stabel & Robbe-Austerman (2011) 
    Mycobacterium leprae Monocyte 2010 Sinsimer et al. (2010) 
    Mycobacterium tuberculosis Monocyte; Macrophage; Pleural fluid 2007–2011 Bozza et al. (2007), Rocha-Ramirez et al. (2008), Liang et al. (2011) 
    Neisseria gonorrhoeae Monocyte 2007 Patrone & Stein (2007) 
    Neisseria meningitidis Plasma 2007 Sprong et al. (2007) 
    Orientia tsutsugamushi Serum 2009–2010 Kramme et al. (2009), Iwasaki et al. (2010) 
    Pseudomonas aeruginosa Cornea 2008 Huang et al. (2007) 
    Rickettsia conorii Splenocyte; Serum 2009 Fang et al. (2009) 
    Salmonella Group B Monocyte H; M 2008 Jongyota et al. (2008) 
    Salmonella enterica ser. Dublin (flagellin) Splenocyte 2004 Sbrogio-Almeida et al. (2004) 
    Salmonella muenchen (flagellin) Serum 2001 Eaves-Pyles et al. (2001) 
    Staphylococcus aureus Nasal Polyp; Monocyte, Macrophage H; M 2008–2011 Patou et al. (2008), Chau et al. (2009), Frodermann et al. (2011) 
    Streptococcus pneumoniae Macrophage; T Cell H; M 2009–2011 Bogaert et al. (2009), Ota et al. (2011) 
    Streptococcus pyogenes Macrophage; Plasma; Serum H; M 2007–2011 Goldmann et al. (2007), Wang et al. (2008), Saito et al. (2011) 
    Streptococcus agalactiae Serum 2007–2011 Madureira et al. (2007, 2011) 
    Yersinia enterocolitica Macrophage 2007 McNally et al. (2007) 
Type of microbe and pathogen Cellular or tissue source of IL-10 Species Year References 
Protozoa 
    Leishmania amazonensis Dendritic Cell 2007 Xin et al. (2007) 
    Leishmania braziliensis Monocyte; Macrophage 2010 Vargas-Inchaustegui et al. (2010) 
    Leishmania chagasi Macrophage; T Cell 2008 Ettinger & Wilson (2008) 
    Leishmania donovani Dermal Lesion 2011 Katara et al. (2011) 
    Leishmania guyanensis CD45RA(−) CD4(+)/CD8(+) T Cell 2007 Bourreau et al. (2007) 
    Leishmania major Dendritic Cell 2007 Xin et al. (2007) 
    Plasmodium spp. Plasma 2010 Han et al. (2010) 
    Schistosoma japonicum CD4(+) CD25(+) T Cell 2007 Yang et al. (2007) 
    Toxoplasma gondii Splenocyte 2010 Guiton et al. (2010) 
    Trypanosoma brucei Plasma 2010 Morrison et al. (2010) 
    Trypanosoma cruzi Splenocyte 2010 Rodrigues et al. (2010) 
Nematodes and fungi 
    Heligmosomoides polygyrus Monocyte; T Cell H; M 2007 Setiawan et al. (2007), Rocha-Ramirez et al. (2008) 
    Paracoccidioides brasiliensis Monocyte; Dendritic Cell H; M 2007 Ferreira et al. (2007), Kurokawa et al. (2007) 
    Paracoccidioides brasiliensis Vaccine Lung Extracts 2009 Braga et al. (2009) 
Viruses 
    Chikungunya Virus Plasma; Serum 2011 Kelvin et al. (2011), Wauquier et al. (2011) 
    Crimean-Congo Haemorrhagic Fever Virus Plasma 2010 Saksida et al. (2010) 
    Cytomegalovirus Plasma; Serum 2010 Waters et al. (2010) 
    Epstein–Barr Virus Nasopharyngeal Carcinoma; Plasma 2007–2009 Ogino et al. (2007), Wingate et al. (2009) 
    Herpesvirus-6 Cerebrospinal Fluid 2010 Kawabe et al. (2010) 
    Human Immunodeficiency virus Cervicovaginal Lavage; Plasma 2008–2009 Bebell et al. (2008), Barqasho et al. (2009) 
    Human Papilloma Virus Dendritic Cell 2007 De Witte et al. (2007) 
    Tacaribe Virus Monocyte; Macrophage 2011 Groseth et al. (2011) 
Bacteria 
    Bacteroides fragilis Serum 2011 Cohen-Poradosu et al. (2011) 
    Borrelia burgdorferi Macrophage H; M 2008–2009 Lazarus et al. (2008), Strle et al. (2009) 
    Borrelia turicatae Plasma; Brain and Heart Tissue 2007 Gelderblom et al. (2007) 
    Burkholderia pseudomallei Splenocyte; Hepatocyte; Dendritic Cell 2000–2011 Ulett et al. (2000, 2005), Williams et al. (2011) 
    Chlamydia pneumoniae Monocyte; Macrophage; T Cell; Gingival Fibroblast M; H 2008–2011 Mamata et al. (2007), Rizzo et al. (2008), Bermudex-Fajardo et al. (2011) 
    Chlamydia trachomatis Cervical Lymphocyte; Conjunctival Mucosa; Macrophage 2007–2011 Vats et al. (2007), Skwor et al. (2008), Agrawal et al. (2009a, b), Azenabor et al. (2011) 
    Chlamydia muridarum Plasmacytoid Dendritic Cell 2009 Moniz et al. (2009) 
    Escherichia coli Bladder; Monocyte; Urine Stool M; H 2010–2011 Jongyota et al. (2008), Long et al. (2010), Duell et al. (2012) 
    Helicobacter pylori Macrophage; Plasma H; M 2007–2008 Obonyo et al. (2007), Kayhan et al. (2008) 
    Legionella pneumophila Macrophage; Epithelial Cell 2011 McCoy-Simandle et al. (2011) 
    Leptospira biflexa Monocyte H; M 2008 Jongyota et al. (2008) 
    Leptospira interrogans Monocyte; Spleenocyte; Whole Blood H; M; Ha 2008–2011 Jongyota et al. (2008), Vernel-Pauillac & Goarant (2010) 
    Mycobacterium avium Monocyte 2008–2011 Souza et al. (2008), Stabel & Robbe-Austerman (2011) 
    Mycobacterium leprae Monocyte 2010 Sinsimer et al. (2010) 
    Mycobacterium tuberculosis Monocyte; Macrophage; Pleural fluid 2007–2011 Bozza et al. (2007), Rocha-Ramirez et al. (2008), Liang et al. (2011) 
    Neisseria gonorrhoeae Monocyte 2007 Patrone & Stein (2007) 
    Neisseria meningitidis Plasma 2007 Sprong et al. (2007) 
    Orientia tsutsugamushi Serum 2009–2010 Kramme et al. (2009), Iwasaki et al. (2010) 
    Pseudomonas aeruginosa Cornea 2008 Huang et al. (2007) 
    Rickettsia conorii Splenocyte; Serum 2009 Fang et al. (2009) 
    Salmonella Group B Monocyte H; M 2008 Jongyota et al. (2008) 
    Salmonella enterica ser. Dublin (flagellin) Splenocyte 2004 Sbrogio-Almeida et al. (2004) 
    Salmonella muenchen (flagellin) Serum 2001 Eaves-Pyles et al. (2001) 
    Staphylococcus aureus Nasal Polyp; Monocyte, Macrophage H; M 2008–2011 Patou et al. (2008), Chau et al. (2009), Frodermann et al. (2011) 
    Streptococcus pneumoniae Macrophage; T Cell H; M 2009–2011 Bogaert et al. (2009), Ota et al. (2011) 
    Streptococcus pyogenes Macrophage; Plasma; Serum H; M 2007–2011 Goldmann et al. (2007), Wang et al. (2008), Saito et al. (2011) 
    Streptococcus agalactiae Serum 2007–2011 Madureira et al. (2007, 2011) 
    Yersinia enterocolitica Macrophage 2007 McNally et al. (2007) 

H, Human; M, Mouse; C, Cow; Ha, Hamster.

Cellular sources of IL-10 and mechanisms of action

Interleukin-10 is a 37-kDa protein that exists as a homodimer of two 18.5-kDa parts (Fiorentino et al., 1989; Vieira et al., 1991). Five paralogues of IL-10, namely IL-19, IL-20, IL-22, IL-24 and IL-26 (Mege et al., 2006), along with IL-28 and IL-29 comprise the ‘IL-10 Family’ of which IL-10 is the founding member (Moore et al., 2001; Mosser & Zhang, 2008). IL-10 is derived from a number of cellular sources relating to the type of infection, the type of host cell that the microorganism or foreign epitope comes into contact with, and the signal transduction pathway(s) initiated (Moore et al., 2001; O'Garra et al., 2004). It is sourced principally from monocytes/macrophages, dendritic cells, CD4(+) and T-reg lymphocytes during or shortly after antigen presentation (Ettinger et al., 1995; Bourreau et al., 2007; Bozza et al., 2007; De Witte et al., 2007; Ferreira et al., 2007; Goldmann et al., 2007; Kurokawa et al., 2007; McNally et al., 2007; Obonyo et al., 2007; Patrone & Stein, 2007; Setiawan et al., 2007; Xin et al., 2007; Yang et al., 2007; Couper et al., 2008a, b; Jongyota et al., 2008; Lazarus et al., 2008; Rocha-Ramirez et al., 2008; Souza et al., 2008; Bogaert et al., 2009; Fang et al., 2009; Strle et al., 2009; Sinsimer et al., 2010; Vargas-Inchaustegui et al., 2010; Groseth et al., 2011; McCoy-Simandle et al., 2011; Ota et al., 2011; Stabel & Robbe-Austerman, 2011).

Mechanistically, IL-10 promotes B lymphocyte proliferation by altering the Th cell environment and suppresses inflammation and macrophage activity by inhibiting the production of interferon (IFN)-gamma, IL-2, IL-12, IL-18 and tumour necrosis factor (TNF)-alpha as well as other cytokines (Moore et al., 2001; Couper et al., 2008a, b). Thus, the cytokines action towards pathogenesis during infection are believed to hinge on microorganism clearance by stimulating adaptive immune effector mechanisms involving clonal proliferation and maturation of Th2 lymphocytes as recently reviewed elsewhere (Ouyang et al., 2011). The suppressive influence of IL-10 towards macrophages and Th1 responses enables Th2 responses, characterized by IL-4, IL-5, IL-6 and IL-13 (Couper et al., 2008a, b). This effect on humoral effector mechanisms related to B lymphocytes, antibody production and alternately activated macrophages (Couper et al., 2008a, b) is important in the resolution of some infections such as helminth and protozoan infections, excluding malaria (Bate et al., 1992; Stijlemans et al., 2007). IL-10 may also work in concert with transforming growth factor (TGF)-β to suppress Th1 and Th2 responses through a Th3 response (Cools et al., 2008). While TGF-β maintains T lymphocyte tolerance to antigens via its direct effects on the differentiation of T effector lymphocytes (T-eft) and T regulatory (T-reg) lymphocytes, IL-10 operates as a feedback inhibitor of T lymphocyte responses. Together, both activities appear to control inflammatory responses triggered by microbial insult (Li & Flavell, 2008). The mechanisms of action of IL-10 was also described recently in terms of its effects on T-reg and Th0 cells, leading to the down-regulation or destruction of T-eft lymphocytes (Fuchs et al., 2009). While T-reg lymphocytes such as natural T-reg cells are critical in some infections such as helminth infections, a subset of T-reg cells, Type 1 regulatory T (Tr1) lymphocytes, are produced in response to bacterial infection of dendritic cells (McGuirk et al., 2002). Tr1 lymphocytes suppresses Th1 responses triggered by pathogen stimulation (Groux et al., 1997) along with other T-reg lymphocytes through the T cell receptor (TCR) (Roncarolo et al., 2006). This causes IL-10 and TGF-β synthesis that down-regulates pro-inflammatory cytokines and CD8+ T lymphocyte proliferation. In turn, this down-regulates CTLs, NK cells and large granular lymphocytes, which comprise the T-eft lymphocyte group (Wu et al., 2007).

In terms of timing, the early phase of infection is the key stage at which an inflammatory, regulatory and/or memory response is preferentially induced (Moreira et al., 2008) and recent studies have shown that this is when IL-10 can radically influence ensuing responses (Xin et al., 2007; Zheng et al., 2009). Challenge with microorganisms or microbial extracts can up-regulate both pro-inflammatory cytokines (TNF-alpha and IL-12) and IL-10, demonstrating that concurrent induction of conflicting responses early in the response to microorganisms can occur (De Witte et al., 2007; Rocha-Ramirez et al., 2008). IL-10 at the early stages of infection can drive the developing immune response from a CMI pro-inflammatory one, to a pro-regulatory, humoral response useful for orchestrating antibody-driven resolution of infection. As a result of the early regulatory role of IL-10 in host responses to infection inappropriate timing or degrees of production can lead to ineffective pathogen clearance and, as a result, persistent infection. In other words, the nature of IL-10 on a sliding scale of pro-inflammatory and pro-memory responses means that poorly timed or poorly controlled degrees of synthesis can hamper disease resolution. IL-10 produced too early prompts an inappropriately timed change from CMI to humoral responses, and too much IL-10 can cause persistent or chronic infection (McGuirk et al., 2002). In such cases, less inflammation fails to promote microbial clearance because the stage of the infection is too early for effective B lymphocyte-mediated Ag-specific responses (McGuirk et al., 2002). Examples of deregulated IL-10 early during infection that leads to poor antimicrobial effector mechanisms, increased disease severity and chronicity include Pseudomonas aeruginosa lung infection (Chmiel et al., 1999), colitis (Kullberg et al., 2002) and malaria (Plebanski et al., 1999; Couper et al., 2008a, b). A contrasting, defensive role for early IL-10 produced immediately after infection with uropathogenic Escherichia coli was shown in a recent study on cystitis (Duell et al., 2012) underscoring the complexity of early IL-10 effects on host defence in the first few hours after acute bacterial infection.

At the signalling level, IL-10 inhibits transcription of pro-inflammatory cytokines, and post-transcriptional events associated with their actions via mechanisms such as mRNA degradation (Bogdan et al., 1992; Wang et al., 1994; Aste-Amezaga et al., 1998; Kishore et al., 1999; Kontoyiannis et al., 2001; Zhou et al., 2004). This has been shown in studies using LPS (Wang et al., 1994; Niiro et al., 1995; Brown et al., 1996; Dokter et al., 1996; Lentsch et al., 1997; Song et al., 1997; Zhou et al., 2004). IL-10 induces suppressor of cytokine signalling (Socs)-1 and Socs-3, and roles for janus kinase 1, tyrosine kinase 2, signal transducers and activators of transcription (Stat)-1, Stat-3 and Stat-5 in downstream signalling events are beyond the scope of this review and described elsewhere (Grutz, 2005). In terms of signal transduction, IL-10 effects phosphoinositide 3-kinase and Akt (Murphy et al., 1994; Bhattacharyya et al., 2004) but there remains debate on the influence of IL-10 on p39 mitogen activated protein kinase and nuclear factor-KappaB (NF-kB) (Wang et al., 1995; Dokter et al., 1996; Song et al., 1997; Clarke et al., 1998; Denys et al., 2002). Regarding NF-kB activity, IL-10 appears to alter the composition of NF-kB from transactivating p65/p50 heterodimers to inhibitory p50/p50 homodimers (Driessler et al., 2004). Overall, however, the molecular mechanisms underlying the signalling events that lead to IL-10′s anti-inflammatory actions are not entirely clear.

Newly discovered microbial triggers of IL-10 in the host

Certain pathogens can trigger selected cytokine production pathways in a manner that favours their survival within the host and IL-10 is increasingly associated with such virulence strategies (Mege et al., 2006; Rahman & McFadden, 2006). Antigen-presenting cells (APCs) such as macrophages, monocytes and dendritic cells use Fc and other receptors to detect microorganisms and secrete IL-10 in response to organisms, including salmonella, yersinia, neisseria, helicobacter, leishmania and mycobacteria as well as nematodes, fungi, viruses and pathogenic protozoa (Table 1). The IL-10 that is produced by these APCs and other cells during infection influences cell activation and differentiation (Edwards et al., 2006) and can alter cell population responses to infection (Katakura et al., 2004). A number of studies on Gram-positive and Gram-negative bacteria and Chlamydia in the last few years in particular have shed new light onto how IL-10 is induced in response to these pathogens and what its production means for pathogenesis.

IL-10 induced by Gram-positive bacteria, including streptococci and staphylococci, has major implications for the hosts' ability to control these organisms at mucosal sites of infection. Type-II activated macrophages, defined elsewhere (Edwards et al., 2006; Gordon & Martinez, 2010), produce IL-10 in response to streptococci. This leads to anti-inflammatory effects via Th2 lymphocytes in a response that mediates tissue repair and regeneration in infection rather than phagocytosis, which may prolong microorganism clearance. IL-10 from macrophages is secreted into serum in response to Streptococcus pyogenes M protein (Price et al., 2005). The M protein, which may impact host cell apoptosis, as reviewed elsewhere (Ulett & Adderson, 2006), binds to CD46 and the TCR and binding to naïve CD4+ T lymphocytes initiates induction of Tr1 cells. This causes IL-10 synthesis (Price et al., 2005). Here, the IL-10 may promote a delayed immune response and enable the bacteria to colonize the host more effectively, thus increasing the magnitude of infection (Price et al., 2005). Streptococcus pneumoniae also triggers IL-10 in macrophages and T lymphocytes (Table 1), which is associated with impaired innate and acquired cellular responses to this organism in neonatal and infant mice (Ota et al., 2011). However, early IL-10 triggered by Streptococcus agalactiae was recently shown to play a role in shaping protective immune responses against this organism through effects on neutrophil trafficking (Madureira et al., 2011). Other defence mechanisms related to streptococci at the mucosa encompass complement/CD46-induced T-reg cells (cT-reg), which are capable of promoting antibody production via IL-10 signalling and cell–cell contact (Fuchs et al., 2009). CD25 and CD137 may provide a switch for such responses as their expression coincides with fewer T-eft cells and B lymphocyte activation via CD46 stimulation/high IL-10 levels (Fuchs et al., 2009).

Aside from streptococcal M protein being a significant epitope for IL-10 stimulation, recent evidence has highlighted a role for staphylococcal peptidoglycan as a moderator of T lymphocyte-mediated toxic shock syndrome (Chau et al., 2009; Frodermann et al., 2011). Staphylococcus aureus induces IL-10 in monocytes and macrophages (but not dendritic cells) after recognition of peptidoglycan-embedded lipopeptides and glycopolymers in the bacterial cell wall (Table 1) (Frodermann et al., 2011). Toll-like Receptor (TLR)2 signalling stimulates the IL-10 production, however, when the same interaction occurs with dendritic cells, an IL-12 pro-inflammatory response is initiated (Frodermann et al., 2011). Thus, this response is dependent upon the type of APC-peptidoglycan interaction. In this case, peptidoglycan-rich Gram-positive species may down-regulate inflammation when present in large quantities, to counteract the effect of other pro-inflammatory antigens (Gjertsson et al., 2002; Chau et al., 2009). This, as a result, may influence pathogen clearance. It is therefore reasonable to assume that such differential APC responses in terms of IL-10 production may account for divergent staphylococcal disease outcomes in different tissues and infection sites (Chau et al., 2009; Frodermann et al., 2011). A recent suggestion of IL-10-centric suppressive effects mediated by mass Gram-positive peptidoglycan/cell wall components at the enteric mucosa (Chau et al., 2009) parallels the biology of host responses to LPS in this way, wherein IL-10 modulates overactive immune responses and limits inflammation triggered by Gram-negative organisms (Donnelly et al., 1999; Moore et al., 2001). Together, these data also highlight the function of IL-10 in maintaining the balance of normal flora within mucosal sites, such as the gastrointestinal and genitourinary tracts. Genetic evidence of this function is seen in IL-10-deficient mice that exhibit colitis because of immune dysregulation, altered normal flora, and complex IL-10-related colitogenic effects (Mahler et al., 2002).

For Gram-negative pathogens, microorganism load can influence IL-10 responses during certain infections, where higher bacterial burdens promote IL-10 production, in contrast to lower burdens that appear to induce IL-12 pro-inflammatory responses. For Helicobacter pylori, this occurs in a partially MyD88/TLR4-dependent fashion (Obonyo et al., 2007). These findings support the concept that variable conditions of APC activation play a role in regulating the type of inflammatory response involving IL-10 during infection, as discussed for staphylococcal peptidoglycan. For Salmonella and Yersinia, subcomponents of the organisms' flagella, displayed on the cell surface and used for motility, have been shown to influence IL-10 production in the host under distinct conditions. On the one hand, live flagellated Salmonella induce Th1 activity, but non-native, soluble FliC flagellar protein (the major component of the flagella apparatus) induces a Th2 type host response (Cunningham et al., 2004). This example underscores the divergent APC polarization responses that can occur for inflammatory or suppressive effects depending on the nature of the foreign antigen encounter. Other studies have demonstrated that Salmonella flagella trigger IL-10 secretion in spleenocytes (Sbrogio-Almeida et al., 2004), monocytes (Ciacci-Woolwine et al., 1997; Wyant et al., 1999) and in serum of infected mice (Eaves-Pyles et al., 2001). In contrast, when expressed in a Paracoccidioides brasiliensis vaccine antigen, Salmonella enterica FliC appears to dampen IL-10 production in the lungs of immunized mice (Braga et al., 2009) (Table 1). Flagella produced by Yersinia enterocolitica were also recently associated with IL-10 induction in human macrophages (McNally et al., 2007). Mechanistically, the immune modulatory effects of Gram-negative bacterial flagella towards IL-10 synthesis presumably occur through TLR5, as demonstrated for other cytokines such as IL-6 (Hayashi et al., 2001; Andersen-Nissen et al., 2005) although this has not yet been demonstrated.

There are a number of chlamydial antigens associated with the production of IL-10 in macrophages and T lymphocytes, the most studied being the major outer membrane protein (MOMP) (Vats et al., 2007; Azenabor et al., 2011; Bermudex-Fajardo et al., 2011). IL-10 secretion can have both positive and detrimental effects on chlamydial persistence during infection (Thiel et al., 2000; Bandholtz et al., 2002). The negative effects of IL-10 production stem from its immune modulatory effect of suppressing the production of IFN-γ, a cytokine required for effective clearance of Chlamydia from tissues. Contrasting positive effects also stem from the anti-inflammatory influences of IL-10, because of reduced severe pathological sequelae associated with infection. An effect related to both consequences, however, is that IL-10 also reduces the chances of IFN-γ-mediated chlamydial persistence during infection, which is an interaction largely related to tryptophan, although RNS may play a role as well, as discussed below (Rottenberg et al., 2002).

At the cellular level, IL-10 may inhibit several antimicrobial activities in APCs such as fusion of vacuoles with lysosomes and IFN-γ-mediated intracellular tryptophan depletion, which could provide an opportunity for chlamydial persistence in host cells. IL-10 is known to effect both of these pathways in other systems (MacKenzie et al., 2003; Weiss et al., 2005); firstly, by restricting phagolysosomal maturation (Coutinho-Silva et al., 2003; O'Leary et al., 2011), and secondly, by suppressing the production of IFN-γ, which inhibits bacterial acquisition of host cell tryptophan via the activation of indoleamine 2,3-dioxygenase (Ibana et al., 2011). Intracellular Chlamydia are also killed in APCs by nitric oxide (NO) under certain circumstances (Gold et al., 2004), and NO (Rottenberg et al., 1999; Carratelli et al., 2005; Jayarapu et al., 2010) and iNOS (Ramsey et al., 2001; Rothfuchs et al., 2001; Shimada et al., 2011) induction has been associated with anti-Chlamydophila pneumoniae, as well as pathological (Huang et al., 2002) effects. The influence that IL-10 might exert over these mechanisms of intracellular killing of Chlamydia, however, is unclear. IL-10 down-regulates NO induced by other pathogens including P. brasiliensis (Moreira et al., 2010) and parasites (Gazzinelli et al., 1992), and macrophages deficient in IL-10 kill C. pneumoniae better than the wild-type macrophages, which appears to be related to iNOS (Rothfuchs et al., 2001). In addition, mechanisms of host cell death, which are effected by NO in other infections (Ulett & Adderson, 2005), are modulated by Chlamydia in various cell types including epithelial cells, T lymphocytes, and macrophages (Yaraei et al., 2005; Huston et al., 2011; Olivares-Zavaleta et al., 2011). Modulation of host cell death (including inhibition of) by Chlamydia has also been linked to altered redox (Sessa et al., 2009) and ROS (Vardhan et al., 2010), among other mechanisms as reviewed elsewhere (Sharma & Rudel, 2009). To date, however, there are few studies that have explored the regulation of cell death responses in relation to NO or IL-10 during chlamydial infection.

Also in terms of chlamydial persistence, conditions relating to monocytes, T lymphocytes and a combination of high IL-10 and low TNF-α levels are themes among several studies (Holland et al., 1996; Yin et al., 1997; Braun et al., 1999; Giraldo et al., 1999; Kinnunen et al., 2003; Appel et al., 2004). In one infection model, IL-10-deficient mice demonstrated accelerated clearance of Chlamydia trachomatis infection, which correlated with a lack of a fibrotic tissue. This study suggested that IL-10 might have interfered with T lymphocyte-driven Th1 responses, leading to an increased susceptibility to re-infection (Yang et al., 1999). In addition to MOMP, chlamydial recurrence has also been linked to Heat Shock Protein-60 (HSP-60) (Kinnunen et al., 2003). Another study showed that CD4+ T lymphocytes help control persistent infection during the later stages of disease (Morrison & Morrison, 2000), and, more recently, Tr1-mediated IL-10 pathways were implicated in persistence (Appel et al., 2004). Finally, steroid hormones including β-estradiol may also influence the role of IL-10-mediated immune responses in chlamydial persistence because these correlate with IL-10 levels during C. trachomatis infection and fertility disorders (Kaushic et al., 2000; Agrawal et al., 2007, 2009a, b). Thus, in addition to effects on intracellular killing mechanisms as discussed earlier, IL-10 may contribute to chlamydial survival in the host by suppressing Th1 responses, mediating Tr1 pathways, and may be affected by hormonal mechanisms within the reproductive cycle that are important in C. trachomatis persistence.

Both monocytes and T lymphocytes generate IL-10 in response to C. pneumoniae (Mamata et al., 2007) but fail to do so when stimulated with a single chlamydial antigen such as MOMP. The lack of response to such an immunogenic antigen in single-lineage monocyte or T lymphocyte exposure models may indicate cell-specific actions of MOMP (Vats et al., 2007; Azenabor et al., 2011) or may reflect inherent intercellular communication effects. Here, it is important to highlight the role of intercellular interactions in studies of responses to infection because such cellular communications are often essential to drive host-pathogen dynamics. This has been shown for optimal cytokine production, microorganism transfer between host cells (Vanham et al., 2000), bacterial killing (Ulett et al., 1998) and apoptosis during infection (Sharma et al., 2009), as recently reviewed elsewhere (Duell et al., 2011). Further to the divergent effects of whole C. pneumoniae and MOMP towards monocyte and T lymphocyte-derived IL-10 are varied effects of viable and killed C. pneumoniae. While stronger Th1 responses are associated with live C. pneumoniae (Mamata et al., 2007), killed bacteria cause directed Th2 responses. This is probably related to the unique developmental life cycles of Chlamydia, where extracellular and intracellular forms exist and require two different types of immune responses to be initiated for eradication. Thus, seemingly conflicting chlamydial triggers of IL-10 synthesis based on pathogen form reflect the essential plasticity of host responses towards this organism at different stages of infection.

In addition to macrophages, dendritic cells produce IL-10 in response to Chlamydia. A plasmocytoid dendritic cell subset is especially predisposed to IL-10 production stemming from Chlamydia muridarum elementary body infection (Moniz et al., 2009). Classical dendritic cells, in contrast, fail to make IL-10 during equivalent infection and instead generate Th1-centric responses in vivo. This suggests that the early stimulatory events of dendritic cell activation during C. muridarum infection drive different facets of pathogenesis (Moniz et al., 2009). For example, the shaping of IL-10 suppressive effects by plasmocytoid dendritic cells may influence the role of IL-17 during infection (Bai et al., 2009), which modulates the Th1 developmental activities of dendritic cells when in co-culture with T lymphocytes. Altered dendritic cell populations and subsequent effects on IL-10 may also relate to locational bias in host tissues during chlamydial infection. In this regard, recent findings of divergent Th1 and Th2 responses in distinct areas of the genital tract during chlamydial infection, for example, may reflect local dendritic cell activities and IL-10 effects (Marks et al., 2010). Notably, NK cells also play a role in the balance of Th cell responses when co-cultured with dendritic cells during C. muridarum infection and exhibit robust responses that could influence pathogenesis (Jiao et al., 2011). In these systems, the triggers of IL-10 may not denote simple bacterial–host receptor interactions but rather, intercellular synergies between host cells that may indirectly modify signalling in defence pathways. Finally, C. pneumoniae was also reported to stimulate IL-10 in a recent study on gingival fibroblasts (Table 1), which has implications for the pathogenesis of chlamydial oral disease.

In terms of protozoan factors that stimulate IL-10 production, numerous recent studies have demonstrated that IL-10 is triggered by Leishmania spp., Plasmodium spp., Schistosoma japonicum, Toxoplasma gondii and Trypanosoma spp. (Table 1). The specific protozoan components that induce the IL-10 in monocytes, macrophages, T lymphocytes and plasma in the host response to these pathogens, however, is not clear. Recent studies on cytokine stimulation in response to Leishmania spp. have focused on candidate vaccines and prophylactic measures to generate Th1-centric inflammatory responses (Bacellar et al., 2000; Murphy et al., 2001). Findings on the immunogenicity of whole cell extracts or protein fractions have indicated induction of IL-10 in macrophages and dendritic cells by Leishmania Eukaryotic Initiation Factor (LeiF) (Skeiky et al., 1995; Probst et al., 1997; Barhoumi et al., 2011) in conjunction with IL-12/Th1 responses. Leishmania infantum LeiF induces variable levels and ratios of IL-10, IL-12 and TNF-α dependent upon the specific antigenic peptide fragment used for stimulation (Barhoumi et al., 2011). Here, the ability of the one protein (i.e. Leif) to generate opposing cytokine responses may reflect distinct conditions of APC activation, or may indicate limitations of the in vitro testing approach used for these studies. In vivo testing of different peptide fragments would be valuable to investigate these results and provide new insight into the effects of single proteins and peptides on the strength of IL-10 feedback loops within broader Th1 and Th2 cytokine responses. Finally, Th1/Th2 switching through up-regulation of IL-10 was recently shown in Heligmosomoides polygyrus infection in which anti-IL-10R antibody reversed the response and up-regulated inflammation in the intestinal mucosa (Setiawan et al., 2007).

Numerous human viral pathogens have been shown to induce IL-10 in various in vivo studies reported during the past 5 years (Table 1). For viral infections in particular, an intriguing facet of IL-10 mediated immune suppression has become evident from recent observations of cytokine patterns induced by closely related members of the same viral family. Monocytes and macrophages infected with different species of Arenaviridae, for example, exhibit different inflammatory effects dependent upon the viral species traits (Groseth et al., 2011). This illustrates that, even for viruses that are similar in structure and genome organization, the synthesis of IL-10 occurs distinctly and probably hinges on the conditions of APC activation and T-reg lymphocyte activity. In most cases of viral infection, the suppressive effect of the IL-10 produced during infection towards T lymphocyte and pro-inflammatory cytokine activity is not clearly understood.

Finally, as aforementioned, dendritic cells produce IL-10 in response to a number of microorganisms and microbial components, including Leishmania spp., P. brasiliensis and Human Papilloma Virus (Table 1). One particular class of dendritic cells that secretes abundant IL-10 after exposure to LPS is the so-called tolerogenic CD11c(low)CD45RB(high) subset of naturally occurring dendritic cells (Fujita et al., 2006). These IL-10 responses in dendritic cells, similar to those induced in macrophages after Fc receptor binding to LPS (Pengal et al., 2006), probably help to moderate endotoxaemia and peritonitis during disseminated Gram-negative infections. In terms of the response triggered in dendritic cells specifically, TLRs initiate anti-inflammatory responses via IL-10, which promotes IL-10 production by T-reg lymphocytes and this can down-regulate Th1 responses and suppress inflammation (Higgins et al., 2003). IL-10 produced from dendritic cells as a result of bacterial binding to CD46, CD47 or CD61 induces T-reg cells to differentiate into Tr1 cells (Groux et al., 1997), which subsequently secrete IL-10 (McGuirk et al., 2002). This causes a down-regulation of T-eft lymphocytes and CMI responses (Price et al., 2005). Responses such as these could therefore prolong infection in circumstances where CMI responses are unable to effectively reduce pathogen numbers during periods of clonal selection and proliferation.

IL-10 effects on mucosal sIgA

The pathogenesis of infectious disease at mucosal sites involves sIgA, which forms a key defence mechanism in various infections to protect tissue barriers against microbial invasion (Tsuji et al., 2008). IL-10 has a major regulatory role in the development of sIgA responses. Functionally, sIgA, along with T-reg cells, allows mutualism with normal flora at mucosal sites and mediates Ig-dependent defence in these tissues (Brandtzaeg, 2009), which contain most (∼70%) of the Ig-producing cells in the body (Mestecky & Russell, 2000). sIgA-producing plasma cells originate from Gut-associated lymphoid tissues (GALT), bronchus-associated lymphoid tissue (BALT) and the nasopharynx associated lymphoid tissues (NALT) (Mestecky & Russell, 2000). While IgA is predominantly monomeric, in secretions, IgA exists as polymers or dimers, formed through a receptor-mediated mechanism (Woof & Kerr, 2006). Secretion of dimeric IgA occurs via polymeric immunoglobulin receptors (pIgR) that line mucosal epithelial cells and aid in the delivery of polymeric sIgA to the extracellular milieu. CD4+ T lymphocytes help induce IgA by activating B lymphocytes to proliferate and mature in response to T lymphocyte-derived cytokines including IL-10 and others, namely TGF-β, IL-2, IL-5 and IL-6 (Mega et al., 1992; Salvi & Holgate, 1999). sIgA contributes to antimicrobial defence at the mucosa through various mechanisms, as discussed elsewhere (Woof & Kerr, 2006). sIgA binds to Fc alpha receptors on phagocytes to potentiate microbial uptake, and mediates immune exclusion by inhibiting microbial adherence to mucosal epithelium. It also neutralizes viruses, activates alternative complement, and synergizes with nonspecific antimicrobial effectors in airway secretions to kill pathogenic microorganisms (Salvi & Holgate, 1999).

IL-10 is a potent growth factor for B lymphocytes; when these cells are activated through their antigen receptor or CD40, IL-10, together with IL-2 and IL-4, is the key factor that drives secretion of IgA (and also IgM and IgG) (Defrance et al., 1988; Rousset et al., 1991, 1992). IL-10 up-regulates the expression of IL-2 receptors on B lymphocytes and, when derived from Th2 lymphocytes, stimulates early B lymphocyte activation. In this way, IL-10 effects the proliferation and differentiation of B lymphocytes into plasma cells (Fernandez-Botran et al., 1989; Moore et al., 1990; Vieira et al., 1991; Defrance et al., 1992; Rousset et al., 1992) and stimulates terminal differentiation of IgA-producing plasma cells. Il-10 also complements IL-5-driven developmental effects in B1 (CD5+/Ly-1+) lymphocytes (Noelle et al., 1984; Roehm et al., 1984; Go et al., 1990; Ishida et al., 1992; Fluckiger et al., 1993) and, together with TGF-β, stimulates CD40-activated naïve B lymphocytes into isotype switching towards IgA1 and IgA2 production (Salvi & Holgate, 1999).

However, IL-10 displays pleiotropic, suppressive effects towards B lymphocytes and IgA under certain conditions. For example, whereas IL-10 and TGF-β enhance IgA induction in sIgD+ B lymphocytes, IL-10 suppresses IgA production in sIgD B lymphocytes (Defrance et al., 1992). IL-10 has been shown to suppress late B lymphocyte differentiation into Ig-secretory cells (Fiorentini et al., 1989; Go et al., 1990; Moore et al., 1990; Vieira et al., 1991). Activated B lymphocytes that secrete IL-10 may also act to suppress bystander-mediated B lymphocyte activation (Pecanha et al., 1992). This has some similarity to the suppressive effects of IL-10 towards Th1 immune responses where the cytokine alters the environment in which lymphocytes are activated (Fiorentino et al., 1989; Go et al., 1990; Moore et al., 1990; Vieira et al., 1991). Thus, these effects of IL-10 show its complex pleiotropic role in influencing sIgA responses and the related Ig-dependent mechanisms of microbial clearance at mucosal sites. Finally, sIgA may also influence the role of IL-10 itself in antimicrobial defence; in a recent study, mice immunized with recombinant sIgA displayed heightened IL-10 responses in mesenteric lymph nodes and spleen, suggesting that oral immunization promotes IgA switching and increases the production of cytokines systemically that promote the induction of T-eft lymphocytes (Favre et al., 2005).

Insights into IL-10 function in infection from recent probiotic studies

Several clinical and experimental studies conducted over the past 5 years have provided vital insight into the role of IL-10 at mucosal surfaces in the context of microbial probiotics. Probiotics comprise live microorganisms, and, taken as dietary nutrition supplements, can enhance anti-inflammatory responses. This has implications for local and systemic immunity against a multitude of mucosal pathogens. Recently, for example, probiotics have been associated with increased resistance to various infections (Reid et al., 2003; Isolauri & Salminen, 2005), inflammatory bowel disease (Nagalingam & Lynch, 2011; Oliveira et al., 2011; Santos Rocha et al., 2011), urinary tract infections (Anukam et al., 2009; Stapleton et al., 2011), and upper respiratory tract infections (Gleeson et al., 2011; West et al., 2011). In most cases, the underlying molecular and cellular mechanisms behind the apparent immune-boosting effects of probiotics are unclear. On the one hand, these may involve microbial competition whereby probiotics alone, or synergistically with commensal flora, restrict the availability of potential pathogen binding sites on mucosal cells such as intestinal epithelium (Dunne et al., 1999). However, probiotics also undoubtedly stimulate mucosal immune cells and drive immunosuppressive effects (Schiffer et al., 2011). This is evidenced by an increasing number of studies that have illustrated the influence of microorganism probiotics on the production of anti-inflammatory cytokines that mediate the balance of Th1, Th2, Th17 and T-reg responses (Haller et al., 2000; Morita et al., 2002; Dong et al., 2011). Several studies have pinpointed IL-10 as a central player among the anti-inflammatory mediators in the interplay with microbial probiotics.

At the cellular level, the main effects of live microorganism probiotics appear to be the manipulation of T lymphocyte activation and differentiation, inhibition of macrophage function and promotion of T-reg cell development (Kohm et al., 2002; Fujio et al., 2010; Amdekar et al., 2011). Probiotics down-regulate adaptive immune responses and minimize inflammation-induced tissue damage (Moore et al., 2001). This resembles the effect of IL-10 in constraining immunopathology induced by fulminating infection (Brockman et al., 2009; Naicker et al., 2009) and the inhibition of expression of several pro-inflammatory molecules (Moore et al., 2001). In fact, certain probiotic treatments have shown the capacity of controlling specific infectious diseases in an IL-10-dependent manner. This appears to involve a reduction in the secretion of IFN-gamma, TNF-alpha, IL-12 and IL-17, along with an enhanced number of T-reg cells and an up-regulation of TGF-β production in both systemic and mucosal compartment (Di Giacinto et al., 2005; Lavasani et al., 2010; Macho Fernandez et al., 2011).

Other recent findings also point to the fact that IL-10, together with IL-12 and T-reg cells, should be considered a key axis of immune reactivity when evaluating the anti-inflammatory and therapeutic effects of probiotics. Up-regulated IL-10 production, enlarged T-reg cell populations, and down-regulated IL-12 was associated with enhanced protection against infection in live probiotic trials in several animal (Johnson-Henry et al., 2005; Chiba et al., 2010; Weiss et al., 2010; Mohamadzadeh et al., 2011) and human studies (Foligne et al., 2007; Ng et al., 2010). In a mouse model, oral, intranasal and intrarectal delivery of probiotics enhanced protection at mucosal surfaces with up-regulated IL-10 production and CD4+Foxp3+ T-reg populations. Inhibition of effector T lymphocyte development and down-regulation of IL-12 was noted in this model (Mengheri, 2008; Villena et al., 2009; D'Inca et al., 2011). In another study, probiotics provided therapeutic effects in an experimental inflammatory bowel disease model (Kwon et al., 2010). Results consistent with these findings were more recently reported in human studies (Gad et al., 2011; Rutten et al., 2011). Collectively, data from the probiotic field suggest a critical role of IL-10 in maintaining a balance between immune suppression and pro-inflammatory protective immunity in situations of microbial challenge.

Conclusions

Recent insights into newly discovered microbial triggers of IL-10 have important meaning for antimicrobial defence in the early to mid-stages of various infections because of diverse classes of microorganisms, including protozoa, nematodes, fungi, viruses and bacteria. For future studies, it will be essential to tease apart the mechanisms of production, cellular sources and functional impact of microorganism-triggered IL-10 in these infections. Considering the impact of IL-10 on Ag-specific immunity and the importance of its timing of production at the early stages of infection, the temporal kinetics of IL-10 production will also be useful to measure in appropriately characterized models of infection or in clinical studies. A better understanding of these facets of IL-10 in response to its microbial triggers in the near term will aid in further defining the intriguing nature of this key regulator of immune defence in infectious disease.

Conflict of interest

All authors have no conflict of interest.

Acknowledgements

This work was supported by a grant from the Australian National Health and Medical Research Council (569674). G.C.U. is supported by a Future Fellowship (FT110101048) from the Australian Research Council. C.K.T. is a Prime Minister's Endeavour Asia Fellow.

References

Agrawal
T.
Vats
V.
Wallace
P.K.
Salhan
S.
Mittal
A.
(
2007
)
Cervical cytokine responses in women with primary or recurrent chlamydial infection
.
J Interferon Cytokine Res
 
27
:
221
226
.
Agrawal
T.
Vats
V.
Salhan
S.
Mittal
A.
(
2009a
)
Determination of chlamydial load and immune parameters in asymptomatic, symptomatic and infertile women
.
FEMS Immunol Med Microbiol
 
55
:
250
257
.
Agrawal
T.
Gupta
R.
Dutta
R.
Srivastava
P.
Bhengraj
A.R.
Sathan
S.
Mittal
A.
(
2009b
)
Protective or pathogenic immune response to genital chlamydial infection in women-A possible role of cytokine secretion profile of cervical mucosal cells
.
Clin Immunol
 
130
:
347
354
.
Amdekar
S.
Singh
V.
Singh
D.D.
(
2011
)
Probiotic therapy: immunomodulating approach toward urinary tract infection
.
Current Microbiology
 
63
:
484
490
.
Andersen-Nissen
E.
Smith
K.D.
Strobe
K.L.
Barrett
S.L.
Cookson
B.T.
Logan
S.M.
Aderem
A.
(
2005
)
Evasion of Toll-like receptor 5 by flagellated bacteria
.
P Natl Acad Sci USA
 
102
:
9247
9252
.
Anukam
K.C.
Hayes
K.
Summers
K.
Reid
G.
(
2009
)
Probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 may help downregulate TNF-Alpha, IL-6, IL-8, IL-10 and IL-12 (p70) in the neurogenic bladder of spinal cord injured patient with urinary tract infections: a two-case study
.
Adv Urol
 
680363
.
Appel
H.
Neure
L.
Kuhne
M.
Braun
J.
Rudwaleit
M.
Sieper
J.
(
2004
)
An elevated level of IL-10- and TGF beta-secreting T cells, B cells and macrophages in the synovial membrane of patients with reactive arthritis compared to rheumatoid arthritis
.
Clin Rheumatol
 
23
:
435
440
.
Aste-Amezaga
M.
Ma
X.
Sartori
A.
Trinchieri
G.
(
1998
)
Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10
.
J Immunol
 
160
:
5936
5944
.
Azenabor
A.A.
Cintron-Cuevas
J.
Schmitt
H.
Bumah
V.
(
2011
)
Chlamydia trachomatis induces anti-inflammatory effect in human macrophages by attenuation of immune mediators in Jurkat T-cells
.
Immunobiology
 
216
:
1248
1255
.
Bacellar
O.
D'Oliveira
A.
Jr
Jeronimo
S.
Carvalho
E.M.
(
2000
)
IL-10 and IL-12 are the main regulatory cytokines in visceral leishmaniasis
.
Cytokine
 
12
:
1228
1231
.
Bai
H.
Cheng
J.J.
Gao
X.L.
et al
. (
2009
)
IL-17/Th17 promotes Type 1 T cell immunity against pulmonary intracellular bacterial infection through modulating dendritic cell function
.
J Immunol
 
183
:
5886
5895
.
Bandholtz
L.
Kreuger
M.R.
Svanholm
C.
Wigzell
H.
Rottenberg
M.E.
(
2002
)
Adjuvant modulation of the immune responses and the outcome of infection with Chlamydia pneumoniae
.
Clin Exp Immunol
 
130
:
393
403
.
Barhoumi
M.
Garnaoui
A.
Kaabi
B.
Tanner
N.K.
Guizani
I.
(
2011
)
Leishmania infantum LeIF and its recombinant polypeptides modulate interleukin IL-12p70, IL-10 and tumour necrosis factor-alpha production by human monocytes
.
Parasite Immunol
 
33
:
583
588
.
Barqasho
B.
Nowak
P.
Tjernlund
A.
et al
. (
2009
)
Kinetics of plasma cytokines and chemokines during primary HIV-1 infection and after analytical treatment interruption
.
HIV Med
 
10
:
94
102
.
Bate
CAW
Taverne
J.
Roman
E.
Moreno
C.
Playfair
JHL
(
1992
)
Tumor-necrosis-factor induction by malaria exoantigens depends upon phospholipid
.
Immunology
 
75
:
129
135
.
Bebell
L.M.
Passmore
J.A.
Williamson
C.
et al
. (
2008
)
Relationship between levels of inflammatory cytokines in the genital tract and CD4(+) cell counts in women with acute HIV-1 infection
.
J Infect Dis
 
198
:
710
714
.
Bermudex-Fajardo
A.
Stark
A-K.
El-Kadri
R.
et al
. (
2011
)
The effect of Chlamydophila pneumoniae Major Outer Membrane Protein (MOMP) on macrophage and T cell-mediated immune responses
.
Immunobiology
 
216
:
152
163
.
Bhattacharyya
S.
Sen
P.
Wallet
M.
Long
B.
Baldwin
A.S.
Jr
Tisch
R.
(
2004
)
Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IkappaB kinase activity
.
Blood
 
104
:
1100
1109
.
Bisno
A.L.
Brito
M.O.
Collins
C.M.
(
2003
)
Molecular basis of group A streptococcal virulence
.
Lancet Infect Dis
 
3
:
191
200
.
Bogaert
D.
Weinberger
D.
Thompson
C.
Lipsitch
M.
Malley
R.
(
2009
)
Impaired innate and adaptive immunity to Streptococcus pneumoniae and its effect on colonization in an infant mouse model
.
Infect Immun
 
77
:
1613
1622
.
Bogdan
C.
Paik
J.
Vodovotz
Y.
Nathan
C.
(
1992
)
Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10
.
J Biol Chem
 
267
:
23301
23308
.
Bourreau
E.
Ronet
C.
Couppie
P.
Sainte-Marie
D.
Tacchini-Cottier
F.
Launois
P.
(
2007
)
IL-10 producing CD8(+) T cells in human infection with Leishmania guyanensis
.
Microbes Infect
 
9
:
1034
1041
.
Bozza
V.V.
D'Attilio
L.
Mahuad
C.V.
et al
. (
2007
)
Altered cortisol/DHEA ratio in tuberculosis patients and its relationship with abnormalities in the mycobacterial-driven cytokine production by peripheral blood mononuclear cells
.
Scand J Immunol
 
66
:
97
103
.
Braga
C.J.
Rittner
G.M.
Munoz
Henao J.E.
et al
. (
2009
)
Paracoccidioides brasiliensis vaccine formulations based on the gp43-derived P10 sequence and the Salmonella enterica FliC flagellin
.
Infect Immun
 
77
:
1700
1707
.
Brandtzaeg
P.
(
2009
)
Mucosal immunity: induction, dissemination, and effector functions
.
Scand J Immunol
 
70
:
505
515
.
Braun
J.
Yin
Z.N.
Spiller
I.
et al
. (
1999
)
Low secretion of tumor necrosis factor alpha, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis
.
Arthritis Rheum
 
42
:
2039
2044
.
Brockman
M.A.
Kwon
D.S.
Tighe
D.P.
et al
. (
2009
)
IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells
.
Blood
 
114
:
346
356
.
Brown
C.Y.
Lagnado
C.A.
Vadas
M.A.
Goodall
G.J.
(
1996
)
Differential regulation of the stability of cytokine mRNAs in lipopolysaccharide-activated blood monocytes in response to interleukin-10
.
J Biol Chem
 
271
:
20108
20112
.
Carratelli
C.R.
Rizzo
A.
Paolillo
R.
Catania
M.R.
Catalanotti
P.
Rossano
F.
(
2005
)
Effect of nitric oxide on the growth of Chlamydophila pneumoniae
.
Can J Microbiol
 
51
:
941
947
.
Chau
T.A.
McCully
M.L.
Brintnell
W.
et al
. (
2009
)
Toll-like receptor 2 ligands on the staphylococcal cell wall downregulate superantigen-induced T cell activation and prevent toxic shock syndrome
.
Nat Med
 
15
:
641
648
.
Chiba
Y.
Shida
K.
Nagata
S.
et al
. (
2010
)
Well-controlled proinflammatory cytokine responses of Peyer's patch cells to probiotic Lactobacillus casei
.
Immunology
 
130
:
352
362
.
Chmiel
J.F.
Konstan
M.W.
Knesebeck
J.E.
Hilliard
J.B.
Bonfield
T.L.
Dawson
D.V.
Berger
M.
(
1999
)
IL-10 attenuates excessive inflammation in chronic Pseudomonas infection in mice
.
Am J Respir Crit Care Med
 
160
:
2040
2047
.
Ciacci-Woolwine
F.
Kucera
L.S.
Richardson
S.H.
Iyer
N.P.
Mizel
S.B.
(
1997
)
Salmonellae activate tumor necrosis factor alpha production in a human promonocytic cell line via a released polypeptide
.
Infect Immun
 
65
:
4624
4633
.
Clarke
C.J.
Hales
A.
Hunt
A.
Foxwell
B.M.
(
1998
)
IL-10-mediated suppression of TNF-alpha production is independent of its ability to inhibit NF kappa B activity
.
Eur J Immunol
 
28
:
1719
1726
.
Cohen-Poradosu
R.
McLoughlin
R.M.
Lee
J.C.
Kasper
D.L.
(
2011
)
Bacteroides fragilis-stimulated interleukin-10 contains expanding disease
.
J Infect Dis
 
204
:
363
371
.
Cools
N.
Van Tendeloo
VFI
Smits
E.
et al
. (
2008
)
Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4(+) regulatory T cells
.
J Cell Mol Med
 
12
:
690
700
.
Couper
K.N.
Blount
D.G.
Riley
E.M.
(
2008a
)
IL-10: the master regulator of immunity to infection
.
J Immunol
 
180
:
5771
5777
.
Couper
K.N.
Blount
D.G.
Wilson
M.S.
et al
. (
2008b
)
IL-10 from CD4(+)CD25(−)Foxp3(−)CD127(−) adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection
.
PLoS Pathog
 
4
:
13
.
Coutinho-Silva
R.
Stahl
L.
Raymond
M.N.
et al
. (
2003
)
Inhibition of chlamydial infectious activity due to P2X7R-dependent phospholipase D activation
.
Immunity
 
19
:
403
412
.
Cunningham
A.F.
Khan
M.
Ball
J.
Toellner
K.M.
Serre
K.
Mohr
E.
MacLennan
I.C.
(
2004
)
Responses to the soluble flagellar protein FliC are Th2, while those to FliC on Salmonella are Th1
.
Eur J Immunol
 
34
:
2986
2995
.
De Witte
L.
Zoughlami
Y.
Aengeneyndt
B.
David
G.
Kooyk
Y.
Gissmann
L.
Geijtenbeek
TBH
(
2007
)
Binding of human papilloma virus L1 virus-like particles to dendritic cells is mediated through heparan sulfates and induces immune activation
.
Immunobiology
 
212
:
679
691
.
Defrance
T.
Vanbervliet
B.
Pene
J.
Banchereau
J.
(
1988
)
Human recombinant IL-4 induces activated B lymphocytes to produce IgG and IgM
.
J Immunol
 
141
:
2000
2005
.
Defrance
T.
Vanbervliet
B.
Briere
F.
Durand
I.
Rousset
F.
Banchereau
J.
(
1992
)
Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A
.
J Exp Med
 
175
:
671
682
.
Demangel
C.
Bertolino
P.
Britton
W.J.
(
2002
)
Autocrine IL-10 impairs dendritic cell (DC)-derived immune responses to mycobacterial infection by suppressing DC trafficking to draining lymph nodes and local IL-12 production
.
Eur J Immunol
 
32
:
994
1002
.
Denys
A.
Udalova
I.A.
Smith
C.
et al
. (
2002
)
Evidence for a dual mechanism for IL-10 suppression of TNF-alpha production that does not involve inhibition of p38 mitogen-activated protein kinase or NF-kappa B in primary human macrophages
.
J Immunol
 
168
:
4837
4845
.
Di Giacinto
C.
Marinaro
M.
Sanchez
M.
Strober
W.
Boirivant
M.
(
2005
)
Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells
.
J Immunol
 
174
:
3237
3246
.
D'Inca
R.
Barollo
M.
Scarpa
M.
et al
. (
2011
)
Rectal administration of Lactobacillus casei DG modifies flora composition and Toll-like receptor expression in colonic mucosa of patients with mild ulcerative colitis
.
Dig Dis Sci
 
56
:
1178
1187
.
Dokter
W.H.
Koopmans
S.B.
Vellenga
E.
(
1996
)
Effects of IL-10 and IL-4 on LPS-induced transcription factors (AP-1, NF-IL6 and NF-kappa B) which are involved in IL-6 regulation
.
Leukemia
 
10
:
1308
1316
.
Dong
H.
Rowland
I.
Yaqoob
P.
(
2011
)
Comparative effects of six probiotic strains on immune function in vitro
.
Br J Nutr
 
DOI: 10.1017/S0007114511005824
.
Donnelly
R.P.
Dickensheets
H.
Finbloom
D.S.
(
1999
)
The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes
.
J Interferon Cytokine Res
 
19
:
563
573
.
Driessler
F.
Venstrom
K.
Sabat
R.
Asadullah
K.
Schottelius
A.J.
(
2004
)
Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50
.
Clin Exp Immunol
 
135
:
64
73
.
Duell
B.L.
Cripps
A.W.
Schembri
M.A.
Ulett
G.C.
(
2011
)
Epithelial cell coculture models for studying infectious diseases: benefits and limitations
.
J Biomed Biotechnol
 
2011
:
852419
.
Duell
B.L.
Carey
A.J.
Tan
C.K.
et al
. (
2012
)
Innate transcriptional networks activated in bladder in response to uropathogenic Escherichia coli drive diverse biological pathways and rapid synthesis of IL-10 for defense against bacterial urinary tract infection
.
J Immunol
 
188
:
781
792
.
Dunne
C.
Murphy
L.
Flynn
S.
et al
. (
1999
)
Probiotics: from myth to reality. Demonstration of functionality in animal models of disease and in human clinical trials
.
Antonie Van Leeuwenhoek
 
76
:
279
292
.
Eaves-Pyles
T.
Murthy
K.
Liaudet
L.
et al
. (
2001
)
Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation: I kappa B alpha degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction
.
J Immunol
 
166
:
1248
1260
.
Edwards
J.P.
Zhang
X.
Frauwirth
K.A.
Mosser
D.M.
(
2006
)
Biochemical and functional characterization of three activated macrophage populations
.
J Leukoc Biol
 
80
:
1298
1307
.
Ettinger
N.A.
Wilson
M.E.
(
2008
)
Macrophage and T-cell gene expression in a model of early infection with the protozoan Leishmania chagasi
.
PLoS Negl Trop Dis
 
2
:
e252
.
Ettinger
R.
Panka
D.J.
Wang
J.K.
Stanger
B.Z.
Ju
S.T.
Marshak-Rothstein
A.
(
1995
)
Fas ligand-mediated cytotoxicity is directly responsible for apoptosis of normal CD4+ T cells responding to a bacterial superantigen
.
J Immunol
 
154
:
4302
4308
.
Fang
R.
Ismail
N.
Shelite
T.
Walker
D.H.
(
2009
)
CD4(+) CD25(+) Foxp3(−) T-regulatory cells produce both gamma interferon and interleukin-10 during acute severe murine spotted fever rickettsiosis
.
Infect Immun
 
77
:
3838
3849
.
Favre
L.
Spertini
F.
Corthesy
B.
(
2005
)
Secretory IgA possesses intrinsic modulatory properties stimulating mucosal and systemic immune responses
.
J Immunol
 
175
:
2793
2800
.
Fernandez-Botran
R.
Sanders
V.M.
Vitetta
E.S.
(
1989
)
Interactions between receptors for interleukin 2 and interleukin 4 on lines of helper T cells (HT-2) and B lymphoma cells (BCL1)
.
J Exp Med
 
169
:
379
391
.
Ferreira
K.S.
Bastos
K.R.
Russo
M.
Almeida
S.R.
(
2007
)
Interaction between Paracoccidioides brasiliensis and pulmonary dendritic cells induces interleukin-10 production and toll-like receptor-2 expression: possible mechanisms of susceptibility
.
J Infect Dis
 
196
:
1108
1115
.
Fiorentini
C.
Arancia
G.
Paradisi
S.
Donelli
G.
Giuliano
M.
Piemonte
F.
Mastrantonio
P.
(
1989
)
Effects of Clostridium difficile toxins A and B on cytoskeleton organization in HEp-2 cells: a comparative morphological study
.
Toxicon
 
27
:
1209
1218
.
Fiorentino
D.F.
Bond
M.W.
Mosmann
T.R.
(
1989
)
Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones
.
J Exp Med
 
170
:
2081
2095
.
Fleming
S.D.
Leenen
PJM
Freed
J.H.
Campbell
P.A.
(
1999
)
Surface interleukin-10 inhibits listericidal activity by primary macrophages
.
J Leukoc Biol
 
66
:
961
967
.
Fluckiger
A.C.
Garrone
P.
Durand
I.
Galizzi
J.P.
Banchereau
J.
(
1993
)
Interleukin 10 (IL-10) upregulates functional high affinity IL-2 receptors on normal and leukemic B lymphocytes
.
J Exp Med
 
178
:
1473
1481
.
Foligne
B.
Nutten
S.
Grangette
C.
et al
. (
2007
)
Correlation between in vitro and in vivo immunomodulatory properties of lactic acid bacteria
.
World J Gastroenterol
 
13
:
236
243
.
Frodermann
V.
Chau
T.A.
Sayedyahossein
S.
Toth
J.M.
Heinrichs
D.E.
Madrenas
J.
(
2011
)
A modulatory interleukin-10 response to staphylococcal peptidoglycan prevents Th1/Th17 adaptive immunity to Staphylococcus aureus
.
J Infect Dis
 
204
:
253
262
.
Fuchs
A.
Atkinson
J.P.
Fremeaux-Bacchi
V.
Kemper
C.
(
2009
)
CD46-induced human Treg enhance B-cell responses
.
Eur J Immunol
 
39
:
3097
3109
.
Fujio
K.
Okamura
T.
Yamamoto
K.
(
2010
)
The Family of IL-10-secreting CD4+ T cells
.
Adv Immunol
 
105
:
99
130
.
Fujita
S.
Seino
K.
Sato
K.
Sato
Y.
Eizumi
K.
Yamashita
N.
Taniguchi
M.
(
2006
)
Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response
.
Blood
 
107
:
3656
3664
.
Gad
M.
Ravn
P.
Soborg
D.A.
Lund-Jensen
K.
Ouwehand
A.C.
Jensen
S.S.
(
2011
)
Regulation of the IL-10/IL-12 axis in human dendritic cells with probiotic bacteria
.
FEMS Immunol Med Microbiol
 
63
:
93
107
.
Gazzinelli
R.T.
Oswald
I.P.
James
S.L.
Sher
A.
(
1992
)
IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages
.
J Immunol
 
148
:
1792
1796
.
Gelderblom
H.
Schmidt
J.
Londono
D.
et al
. (
2007
)
Role of interleukin 10 during persistent infection with the relapsing fever spirochete Borrelia turicatae
.
Am J Pathol
 
170
:
251
262
.
Giraldo
P.
Neuer
A.
Korneeva
I.L.
Ribeiro
A.
Simoes
J.A.
Witkin
S.S.
(
1999
)
Vaginal heat shock protein expression in symptom-free women with a history of recurrent vulvovaginitis
.
Am J Obstet Gynecol
 
180
:
524
529
.
Gjertsson
I.
Hultgren
O.H.
Tarkowski
A.
(
2002
)
Interleukin-10 ameliorates the outcome of Staphylococcus aureus arthritis by promoting bacterial clearance
.
Clin Exp Immunol
 
130
:
409
414
.
Gleeson
M.
Bishop
N.C.
Oliveira
M.
Tauler
P.
(
2011
)
Daily probiotic's (Lactobacillus casei Shirota) reduction of infection incidence in athletes
.
Int J Sport Nutr Exerc Metab
 
21
:
55
64
.
Go
N.F.
Castle
B.E.
Barrett
R.
et al
. (
1990
)
Interleukin 10, a novel B cell stimulatory factor: unresponsiveness of X chromosome-linked immunodeficiency B cells
.
J Exp Med
 
172
:
1625
1631
.
Gold
E.S.
Simmons
R.M.
Petersen
T.W.
Campbell
L.A.
Kuo
C.C.
Aderem
A.
(
2004
)
Amphiphysin IIm is required for survival of Chlamydia pneumoniae in macrophages
.
J Exp Med
 
200
:
581
586
.
Goldmann
O.
von Kockritz-Blickwede
M.
Holtje
C.
Chhatwal
G.S.
Geffers
R.
Medina
E.
(
2007
)
Transcriptome analysis of murine macrophages in response to infection with Streptococcus pyogenes reveals an unusual activation program
.
Infect Immun
 
75
:
4148
4157
.
Gordon
S.
Martinez
F.O.
(
2010
)
Alternative activation of macrophages: mechanism and functions
.
Immunity
 
32
:
593
604
.
Groseth
A.
Hoenen
T.
Weber
M.
Wolff
S.
Herwig
A.
Kaufmann
A.
Becker
S.
(
2011
)
Tacaribe virus but not Junin virus infection induces cytokine release from primary human monocytes and macrophages
.
PLoS Negl Trop Dis
 
5
:
e1137
.
Groux
H.
Ogarra
A.
Bigler
M.
Rouleau
M.
Antonenko
S.
deVries
J.E.
Roncarolo
M.G.
(
1997
)
A CD4(+) T-cell subset inhibits antigen-specific T-cell responses and prevents colitis
.
Nature
 
389
:
737
742
.
Grutz
G.
(
2005
)
New insights into the molecular mechanism of interleukin-10-mediated immunosuppression
.
J Leukoc Biol
 
77
:
3
15
.
Guiton
R.
Vasseur
V.
Charron
S.
et al
. (
2010
)
Interleukin 17 receptor signaling is deleterious during Toxoplasma gondii infection in susceptible BL6 Mice
.
J Infect Dis
 
202
:
427
435
.
Haller
D.
Bode
C.
Hammes
W.P.
Pfeifer
A.M.
Schiffrin
E.J.
Blum
S.
(
2000
)
Non-pathogenic bacteria elicit a differential cytokine response by intestinal epithelial cell/leucocyte co-cultures
.
Gut
 
47
:
79
87
.
Han
C.
Lin
Y.H.
Shan
G.L.
et al
. (
2010
)
Plasma concentration of malaria parasite-derived macrophage migration inhibitory factor in uncomplicated malaria patients correlates with parasitemia and disease severity
.
Clin Vaccine Immunol
 
17
:
1524
1532
.
Hayashi
F.
Smith
K.D.
Ozinsky
A.
et al
. (
2001
)
The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5
.
Nature
 
410
:
1099
1103
.
Higgins
S.C.
Lavelle
E.C.
McCann
C.
et al
. (
2003
)
Toll-like receptor 4-mediated innate IL-10 activates antigen-specific regulatory T cells and confers resistance to Bordetella pertussis by inhibiting inflammatory pathology
.
J Immunol
 
171
:
3119
3127
.
Holland
M.J.
Bailey
R.L.
Conway
D.J.
et al
. (
1996
)
T helper type-1 (Th1)/Th2 profiles of peripheral blood mononuclear cells (PBMC): responses to antigens of Chlamydia trachomatis in subjects with severe trachomatous scarring
.
Clin Exp Immunol
 
105
:
429
435
.
Huang
J.
DeGraves
F.J.
Lenz
S.D.
et al
. (
2002
)
The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease
.
P Natl Acad Sci USA
 
99
:
3914
3919
.
Huang
X.
Du
W.
Barrett
R.P.
Hazlett
L.D.
(
2007
)
ST2 is essential for Th2 responsiveness and resistance to Pseudomonas aeruginosa Keratitis
.
Invest Ophthalmol Vis Sci
 
48
:
4626
4633
.
Huston
W.M.
Gloeckl
S.
de Boer
L.
Beagley
K.W.
Timms
P.
(
2011
)
Apoptosis is induced in Chlamydia trachomatis-infected HEp-2 cells by the addition of a combination innate immune activation compounds and the inhibitor wedelolactone
.
Am J Reprod Immunol
 
65
:
460
465
.
Ianaro
A.
Tersigni
M.
D'Acquisto
F.
(
2009
)
New insight in LPS antagonist
.
Mini Rev Med Chem
 
9
:
306
317
.
Ibana
J.A.
Belland
R.J.
Zea
A.H.
et al
. (
2011
)
Inhibition of indoleamine 2,3-dioxygenase activity by levo-1-methyl tryptophan blocks gamma interferon-induced Chlamydia trachomatis persistence in human epithelial cells
.
Infect Immun
 
79
:
4425
4437
.
Ishida
H.
Hastings
R.
Kearney
J.
Howard
M.
(
1992
)
Continuous anti-interleukin 10 antibody administration depletes mice of Ly-1 B cells but not conventional B cells
.
J Exp Med
 
175
:
1213
1220
.
Isolauri
E.
Salminen
S.
(
2005
)
Probiotics, gut inflammation and barrier function
.
Gastroenterol Clin North Am
 
34
:
437
450
, viii.
Iwasaki
H.
Mizoguchi
J.
Takada
N.
Tai
K.
Ikegaya
S.
Ueda
T.
(
2010
)
Correlation between the concentrations of tumor necrosis factor-alpha and the severity of disease in patients infected with Orientia tsutsugamushi
.
Int J Infect Dis
 
14
:
E328
E333
.
Jayarapu
K.
Kerr
M.
Ofner
S.
Johnson
R.M.
(
2010
)
Chlamydia-specific CD4 T cell clones control Chlamydia muridarum replication in epithelial cells by nitric oxide-dependent and -independent mechanisms
.
J Immunol
 
185
:
6911
6920
.
Jiao
L.
Gao
X.L.
Joyee
A.G.
et al
. (
2011
)
NK cells promote Type 1 T cell immunity through modulating the function of dendritic cells during intracellular bacterial infection
.
J Immunol
 
187
:
401
411
.
Johnson-Henry
K.C.
Nadjafi
M.
Avitzur
Y.
et al
. (
2005
)
Amelioration of the effects of Citrobacter rodentium infection in mice by pretreatment with probiotics
.
J Infect Dis
 
191
:
2106
2117
.
Jongyota
W.
Wigraipat
C.
Nontapa
S.
Taweechaisupapong
S.
Wara-Aswapati
N.C.
Wongratanacheewin
S.
Sermswan
R.W.
(
2008
)
Differential response of cytokines induced by Leptospira interrogans, serogroup Pomona, serovar Pomona, in mouse and human cell lines
.
Asian Pac J Allergy Immunol
 
26
:
229
236
.
Katakura
T.
Miyazaki
M.
Kobayashi
M.
Herndon
D.N.
Suzuki
F.
(
2004
)
CCL17 and IL-10 as effectors that enable alternatively activated macrophages to inhibit the generation of classically activated macrophages
.
J Immunol
 
172
:
1407
1413
.
Katara
G.K.
Ansari
N.A.
Verma
S.
Ramesh
V.
Salotra
P.
(
2011
)
Foxp3 and IL-10 expression correlates with parasite burden in lesional tissues of post kala azar dermal leishmaniasis (pkdl) patients
.
PLoS Negl Trop Dis
 
5
:
e1171
.
Kaushic
C.
Zhou
F.
Murdin
A.D.
Wira
C.R.
(
2000
)
Effects of estradiol and progesterone on susceptibility and early immune responses to Chlamydia trachomatis infection in the female reproductive tract
.
Infect Immun
 
68
:
4207
4216
.
Kawabe
S.
Ito
Y.
Ohta
R.
Sofue
A.
Gotoh
K.
Morishima
T.
Kimura
H.
(
2010
)
Comparison of the levels of human herpesvirus 6 (HHV-6) DNA and cytokines in the cerebrospinal fluid and serum of children With HHV-6 encephalopathy
.
J Med Virol
 
82
:
1410
1415
.
Kayhan
B.
Arasli
M.
Eren
H.
Aydemir
S.
Aktas
E.
Tekin
I.
(
2008
)
Analysis of peripheral blood lymphocyte phenotypes and Th1/Th2 cytokines profile in the systemic immune responses of Helicobacter pylori infected individuals
.
Microbiol Immunol
 
52
:
531
538
.
Kelvin
A.A.
Banner
D.
Silvi
G.
et al
. (
2011
)
Inflammatory cytokine expression is associated with chikungunya virus resolution and symptom severity
.
PLoS Negl Trop Dis
 
5
:
e1279
.
Kinnunen
A.
Surcel
H.M.
Halttunen
M.
et al
. (
2003
)
Chlamydia trachomatis heat shock protein-60 induced interferon-gamma and interleukin-10 production in infertile women
.
Clin Exp Immunol
 
131
:
299
303
.
Kishore
R.
Tebo
J.M.
Kolosov
M.
Hamilton
T.A.
(
1999
)
Cutting edge: clustered AU-rich elements are the target of IL-10-mediated mRNA destabilization in mouse macrophages
.
J Immunol
 
162
:
2457
2461
.
Kohm
A.P.
Carpentier
P.A.
Anger
H.A.
Miller
S.D.
(
2002
)
Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis
.
J Immunol
 
169
:
4712
4716
.
Kontoyiannis
D.
Kotlyarov
A.
Carballo
E.
et al
. (
2001
)
Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology
.
EMBO J
 
20
:
3760
3770
.
Kramme
S.
An le
V.
Khoa
N.D.
et al
. (
2009
)
Orientia tsutsugamushi bacteremia and cytokine levels in Vietnamese scrub typhus patients
.
J Clin Microbiol
 
47
:
586
589
.
Kullberg
M.C.
Jankovic
D.
Gorelick
P.L.
Caspar
P.
Letterio
J.J.
Cheever
A.W.
Sher
A.
(
2002
)
Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis
.
J Exp Med
 
196
:
505
515
.
Kurokawa
C.S.
Araujo
J.P.
Soares
A.
Sugizaki
M.F.
Peracoli
MTS
(
2007
)
Pro- and anti-inflammatory cytokines produced by human monocytes challenged in vitro with Paracoccidioides brasiliensis
.
Microbiol Immunol
 
51
:
421
428
.
Kwon
H.K.
Lee
C.G.
So
J.S.
et al
. (
2010
)
Generation of regulatory dendritic cells and CD4+Foxp3+ T cells by probiotics administration suppresses immune disorders
.
P Natl Acad Sci USA
 
107
:
2159
2164
.
Latifi
S.Q.
O'Riordan
M.A.
Levine
A.D.
(
2002
)
Interleukin-10 controls the onset of irreversible septic shock
.
Infect Immun
 
70
:
4441
4446
.
Lavasani
S.
Dzhambazov
B.
Nouri
M.
et al
. (
2010
)
A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells
.
PLoS ONE
 
5
:
e9009
.
Lazarus
J.J.
Kay
M.A.
McCarter
A.L.
Wooten
R.M.
(
2008
)
Viable Borrelia burgdorferi enhances interleukin-10 production and suppresses activation of murine macrophages
.
Infect Immun
 
76
:
1153
1162
.
Lentsch
A.B.
Shanley
T.P.
Sarma
V.
Ward
P.A.
(
1997
)
In vivo suppression of NF-kappa B and preservation of I kappa B alpha by interleukin-10 and interleukin-13
.
J Clin Investig
 
100
:
2443
2448
.
Li
M.O.
Flavell
R.A.
(
2008
)
Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10
.
Immunity
 
28
:
468
476
.
Liang
L.
Zhao
Y.L.
Yue
J.
Liu
J.F.
Han
M.
Wang
H.X.
Xiao
H.P.
(
2011
)
Interleukin-10 gene promoter polymorphisms and their protein production in pleural fluid in patients with tuberculosis
.
FEMS Immunol Med Microbiol
 
62
:
84
90
.
Long
K.Z.
Rosado
J.L.
Santos
J.I.
et al
. (
2010
)
Associations between mucosal innate and adaptive immune responses and resolution of diarrheal pathogen infections
.
Infect Immun
 
78
:
1221
1228
.
Macho Fernandez
E.
Valenti
V.
Rockel
C.
Hermann
C.
Pot
B.
Boneca
I.G.
Grangette
C.
(
2011
)
Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide
.
Gut
 
60
:
1050
1059
.
MacKenzie
C.R.
Worku
D.
Daubener
W.
(
2003
)
Regulation of IDO-mediated bacteriostasis in macrophages: role of antibiotics and anti-inflammatory agents
.
Adv Exp Med Biol
 
527
:
67
76
.
Madureira
P.
Baptista
M.
Vieira
M.
et al
. (
2007
)
Streptococcus agalactiae GAPDH is a virulence-associated immunomodulatory protein
.
J Immunol
 
178
:
1379
1387
.
Madureira
P.
Andrade
E.B.
Gama
B.
et al
. (
2011
)
Inhibition of IL-10 production by maternal antibodies against Group B Streptococcus GAPDH confers immunity to offspring by favoring neutrophil recruitment
.
PloS Pathog
 
7
:
1
14
.
Mahler
M.
Most
C.
Schmidtke
S.
Sundberg
J.P.
Li
R.
Hedrich
H.J.
Churchill
G.A.
(
2002
)
Genetics of colitis susceptibility in IL-10-deficient mice: backcross versus F2 results contrasted by principal component analysis
.
Genomics
 
80
:
274
282
.
Maloy
K.J.
Salaun
L.
Cahill
R.
Dougan
G.
Saunders
N.J.
Powrie
F.
(
2003
)
CD4(+)CD25(+) T-R cells suppress innate immune pathology through cytokine-dependent mechanisms
.
J Exp Med
 
197
:
111
119
.
Mamata
Y.
Hakki
A.
Newton
C.
Burdash
N.
Klein
T.W.
Friedman
H.
(
2007
)
Differential effects of Chlamydia pneumoniae infection on cytokine levels in human T lymphocyte- and monocyte-derived cell cultures
.
Int J Med Microbiol
 
297
:
109
115
.
Marks
E.
Tam
M.A.
Lycke
N.Y.
(
2010
)
The female lower genital tract is a privileged compartment with il-10 producing dendritic cells and poor Th1 immunity following Chlamydia trachomatis infection
.
PLoS Pathog
 
6
:
e1001179
.
McCoy-Simandle
K.
Stewart
C.R.
Dao
J.
DebRoy
S.
Rossier
O.
Bryce
P.J.
Cianciotto
N.P.
(
2011
)
Legionella pneumophila Type II secretion dampens the cytokine response of infected macrophages and epithelia
.
Infect Immun
 
79
:
1984
1997
.
McGuirk
P.
McCann
C.
Mills
KHG
(
2002
)
Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis
.
J Exp Med
 
195
:
221
231
.
McNally
A.
La Ragione
R.M.
Best
A.
Manning
G.
Newell
D.G.
(
2007
)
An aflagellate mutant Yersinia enterocolitica biotype 1A strain displays altered invasion of epithelial cells, persistence in macrophages, and cytokine secretion profiles in vitro
.
Microbiology-Sgm
 
153
:
1339
1349
.
Mega
J.
Fujihashi
K.
Kiyono
H.
(
1992
)
Regulation of mucosal immune responses by T lymphocytes: the effect of chronic CD4+ T cell deficiency on IgA synthesis
.
Reg Immunol
 
4
:
70
78
.
Mege
J.L.
Meghari
S.
Honstettre
A.
Capo
C.
Raoult
D.
(
2006
)
The two faces of interleukin 10 in human infectious diseases
.
Lancet Infect Dis
 
6
:
557
569
.
Mengheri
E.
(
2008
)
Health, probiotics, and inflammation
.
J Clin Gastroenterol
 
42
(
Suppl 3 Pt 2
):
S177
S178
.
Mestecky
J.
Russell
M.W.
(
2000
)
Induction of mucosal immune responses in the human genital tract
.
FEMS Immunol Med Microbiol
 
27
:
351
355
.
Mohamadzadeh
M.
Pfeiler
E.A.
Brown
J.B.
et al
. (
2011
)
Regulation of induced colonic inflammation by Lactobacillus acidophilus deficient in lipoteichoic acid
.
P Natl Acad Sci USA
 
108
(
Suppl 1
):
4623
4630
.
Moniz
R.J.
Chan
A.M.
Kelly
K.A.
(
2009
)
Identification of dendritic cell subsets responding to genital infection by Chlamydia muridarum
.
FEMS Immunol Med Microbiol
 
55
:
226
236
.
Moore
K.W.
Vieira
P.
Fiorentino
D.F.
Trounstine
M.L.
Khan
T.A.
Mosmann
T.R.
(
1990
)
Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein–Barr virus gene BCRFI
.
Science
 
248
:
1230
1234
.
Moore
K.W.
de Waal Malefyt
R.
Coffman
R.L.
O'Garra
A.
(
2001
)
Interleukin-10 and the interleukin-10 receptor
.
Annu Rev Immunol
 
19
:
683
765
.
Moreira
L.O.
El Kasmi
K.C.
Smith
A.M.
et al
. (
2008
)
The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls
.
Cell Microbiol
 
10
:
2067
2077
.
Moreira
A.P.
Dias-Melicio
L.A.
Soares
A.M.
(
2010
)
Interleukin-10 but not transforming growth factor beta inhibits murine activated macrophages Paracoccidioides brasiliensis killing: effect on H2O2 and NO production
.
Cell Immunol
 
263
:
196
203
.
Morita
H.
He
F.
Fuse
T.
et al
. (
2002
)
Adhesion of lactic acid bacteria to caco-2 cells and their effect on cytokine secretion
.
Microbiol Immunol
 
46
:
293
297
.
Morrison
S.G.
Morrison
R.P.
(
2000
)
In situ analysis of the evolution of the primary immune response in murine Chlamydia trachomatis genital tract infection
.
Infect Immun
 
68
:
2870
2879
.
Morrison
L.J.
McLellan
S.
Sweeney
L.
Chan
C.N.
MacLeod
A.
Tait
A.
Turner
CMR
(
2010
)
Role for parasite genetic diversity in differential host responses to Trypanosoma brucei Infection
.
Infect Immun
 
78
:
1096
1108
.
Mosser
D.M.
Zhang
X.
(
2008
)
Interleukin-10: new perspectives on an old cytokine
.
Immunol Rev
 
226
:
205
218
.
Murphy
E.E.
Terres
G.
Macatonia
S.E.
et al
. (
1994
)
B7 and interleukin 12 cooperate for proliferation and interferon gamma production by mouse T helper clones that are unresponsive to B7 costimulation
.
J Exp Med
 
180
:
223
231
.
Murphy
M.L.
Wille
U.
Villegas
E.N.
Hunter
C.A.
Farrell
J.P.
(
2001
)
IL-10 mediates susceptibility to Leishmania donovani infection
.
Eur J Immunol
 
31
:
2848
2856
.
Nagalingam
N.A.
Lynch
S.V.
(
2011
)
Role of the microbiota in inflammatory bowel diseases
.
Inflamm Bowel Dis
 
DOI: 10.1002/ibd.21866
.
Naicker
D.D.
Werner
L.
Kormuth
E.
Passmore
J.A.
Mlisana
K.
Karim
S.A.
Ndung'u
T.
(
2009
)
Interleukin-10 promoter polymorphisms influence HIV-1 susceptibility and primary HIV-1 pathogenesis
.
J Infect Dis
 
200
:
448
452
.
Ng
S.C.
Plamondon
S.
Kamm
M.A.
et al
. (
2010
)
Immunosuppressive effects via human intestinal dendritic cells of probiotic bacteria and steroids in the treatment of acute ulcerative colitis
.
Inflamm Bowel Dis
 
16
:
1286
1298
.
Niiro
H.
Otsuka
T.
Tanabe
T.
et al
. (
1995
)
Inhibition by interleukin-10 of inducible cyclooxygenase expression in lipopolysaccharide-stimulated monocytes: its underlying mechanism in comparison with interleukin-4
.
Blood
 
85
:
3736
3745
.
Noelle
R.
Krammer
P.H.
Ohara
J.
Uhr
J.W.
Vitetta
E.S.
(
1984
)
Increased expression of Ia antigens on resting B cells: an additional role for B-cell growth factor
.
P Natl Acad Sci USA
 
81
:
6149
6153
.
Obonyo
M.
Sabet
M.
Cole
S.P.
Ebmeyer
J.
Uematsu
S.
Akira
S.
Guiney
D.G.
(
2007
)
Deficiencies of myeloid differentiation factor 88, toll-like receptor 2 (TLR2), or TLR4 produce specific defects in macrophage cytokine secretion induced by Helicobacter pylori
.
Infect Immun
 
75
:
2408
2414
.
O'Garra
A.
Vieira
P.L.
Vieira
P.
Goldfeld
A.E.
(
2004
)
IL-10-producing and naturally occurring CD4+ Tregs: limiting collateral damage
.
J Clin Invest
 
114
:
1372
1378
.
O'Garra
A.
Barrat
F.J.
Castro
A.G.
Vicari
A.
Hawrylowicz
C.
(
2008
)
Strategies for use of IL-10 or its antagonists in human disease
.
Immunol Rev
 
223
:
114
131
.
Ogino
T.
Moriai
S.
Ishida
Y.
et al
. (
2007
)
Association of immunoescape mechanisms with Epstein–Barr virus infection in nasopharyngeal carcinoma
.
Int J Cancer
 
120
:
2401
2410
.
O'Leary
S.
O'Sullivan
M.P.
Keane
J.
(
2011
)
IL-10 blocks phagosome maturation in mycobacterium tuberculosis-infected human macrophages
.
Am J Respir Cell Mol Biol
 
45
:
172
180
.
Olivares-Zavaleta
N.
Carmody
A.
Messer
R.
Whitmire
W.M.
Caldwell
H.D.
(
2011
)
Chlamydia pneumoniae inhibits activated human T lymphocyte proliferation by the induction of apoptotic and pyroptotic pathways
.
J Immunol
 
186
:
7120
7126
.
Oliveira
M.
Bosco
N.
Perruisseau
G.
et al
. (
2011
)
Lactobacillus paracasei reduces intestinal inflammation in adoptive transfer mouse model of experimental colitis
.
Clin Dev Immunol
 
2011
:
807483
.
Ota
MOC
Oluwalana
C.
Howie
SRC
et al
. (
2011
)
Antibody and T-cell responses during acute and convalescent stages of invasive pneumococcal disease
.
Int J Infect Dis
 
15
:
E282
E288
.
Ouyang
W.
Rutz
S.
Crellin
N.K.
Valdez
P.A.
Hymowitz
S.G.
(
2011
)
Regulation and functions of the IL-10 family of cytokines in inflammation and disease
.
Annu Rev Immunol
 
29
:
71
109
.
Patou
J.
Gevaert
P.
Van Zele
T.
Holtappels
G.
van Cauwenberge
P.
Bachert
C.
(
2008
)
Staphylococcus aureus enterotoxin B, protein A, and lipoteichoic acid stimulations in nasal polyps
.
J Allergy Clin Immunol
 
121
:
110
115
.
Patrone
J.B.
Stein
D.C.
(
2007
)
Effect of gonococcal lipooligosaccharide variation on human monocytic cytokine profile
.
BMC Microbiol
 
7
:
7
.
Pecanha
L.M.
Snapper
C.M.
Lees
A.
Mond
J.J.
(
1992
)
Lymphokine control of type 2 antigen response. IL-10 inhibits IL-5- but not IL-2-induced Ig secretion by T cell-independent antigens
.
J Immunol
 
148
:
3427
3432
.
Pengal
R.A.
Ganesan
L.P.
Wei
G.
Fang
H.Q.
Ostrowski
M.C.
Tridandapani
S.
(
2006
)
Lipopolysaccharide-induced production of interleukin-10 is promoted by the serine/threonine kinase Akt
.
Mol Immunol
 
43
:
1557
1564
.
Plebanski
M.
Flanagan
K.L.
Lee
EAM
et al
. (
1999
)
Interleukin 10-mediated immunosuppression by a variant CD4 T cell epitope of Plasmodium falciparum
.
Immunity
 
10
:
651
660
.
Price
J.D.
Schaumburg
J.
Sandin
C.
Atkinson
J.P.
Lindahl
G.
Kemper
C.
(
2005
)
Induction of a regulatory phenotype in human CD4(+) T cells by streptococcal M protein
.
J Immunol
 
175
:
677
684
.
Probst
P.
Skeiky
Y.A.
Steeves
M.
Gervassi
A.
Grabstein
K.H.
Reed
S.G.
(
1997
)
A Leishmania protein that modulates interleukin (IL)-12, IL-10 and tumor necrosis factor-alpha production and expression of B7-1 in human monocyte-derived antigen-presenting cells
.
Eur J Immunol
 
27
:
2634
2642
.
Rahman
M.M.
McFadden
G.
(
2006
)
Modulation of tumor necrosis factor by microbial pathogens
.
PLoS Pathog
 
2
:
66
77
.
Ramsey
K.H.
Miranpuri
G.S.
Sigar
I.M.
Ouellette
S.
Byrne
G.I.
(
2001
)
Chlamydia trachomatis persistence in the female mouse genital tract: inducible nitric oxide synthase and infection outcome
.
Infect Immun
 
69
:
5131
5137
.
Reid
G.
Sanders
M.E.
Gaskins
H.R.
et al
. (
2003
)
New scientific paradigms for probiotics and prebiotics
.
J Clin Gastroenterol
 
37
:
105
118
.
Rizzo
A.
Paolillo
R.
Lanza
A.G.
Guida
L.
Annunziata
M.
Carratelli
C.R.
(
2008
)
Chlamydia pneumoniae induces interleukin-6 and interleukin-10 in human gingival fibroblasts
.
Microbiol Immunol
 
52
:
447
454
.
Rocha-Ramirez
L.M.
Estrada-Garcia
I.
Lopez-Marin
L.M.
et al
. (
2008
)
Mycobacterium tuberculosis lipids regulate cytokines, TLR-2/4 and MHC class II expression in human macrophages
.
Tuberculosis
 
88
:
212
220
.
Rodrigues
C.M.
Valadares
HMS
Francisco
A.F.
et al
. (
2010
)
Coinfection with different Trypanosoma cruzi strains interferes with the host immune response to infection
.
PLoS Negl Trop Dis
 
4
:
e846
.
Roehm
N.W.
Leibson
H.J.
Zlotnik
A.
Kappler
J.
Marrack
P.
Cambier
J.C.
(
1984
)
Interleukin-induced increase in Ia expression by normal mouse B cells
.
J Exp Med
 
160
:
679
694
.
Roncarolo
M.G.
Gregori
S.
Battaglia
M.
Bacchetta
R.
Fleischhauer
K.
Levings
M.K.
(
2006
)
Interleukin-10-secreting type 1 regulatory T cells in rodents and humans
.
Immunol Rev
 
212
:
28
50
.
Rothfuchs
A.G.
Gigliotti
D.
Palmblad
K.
Andersson
U.
Wigzell
H.
Rottenberg
M.E.
(
2001
)
IFN-alpha beta-dependent, IFN-gamma secretion by bone marrow-derived macrophages controls an intracellular bacterial infection
.
J Immunol
 
167
:
6453
6461
.
Rottenberg
M.E.
Gigliotti Rothfuchs
A.C.
Gigliotti
D.
Svanholm
C.
Bandholtz
L.
Wigzell
H.
(
1999
)
Role of innate and adaptive immunity in the outcome of primary infection with Chlamydia pneumoniae, as analyzed in genetically modified mice
.
J Immunol
 
162
:
2829
2836
.
Rottenberg
M.E.
Gigliotti-Rothfuchs
A.
Wigzell
H.
(
2002
)
The role of IFN-gamma in the outcome of chlamydial infection
.
Curr Opin Immunol
 
14
:
444
451
.
Rousset
F.
Garcia
E.
Banchereau
J.
(
1991
)
Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen
.
J Exp Med
 
173
:
705
710
.
Rousset
F.
Garcia
E.
Defrance
T.
et al
. (
1992
)
Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes
.
P Natl Acad Sci USA
 
89
:
1890
1893
.
Rutten
N.B.
Besseling-Van der Vaart
I.
Klein
M.
De Roock
S.
Vlieger
A.M.
Rijkers
G.T.
(
2011
)
In vitro assessment of the immunomodulatory effects of multispecies probiotic formulations for management of allergic diseases
.
Benef Microbes
 
2
:
183
192
.
Saito
M.
Kajiwara
H.
Iida
K.
Hoshina
T.
Kusuhara
K.
Hara
T.
Yoshida
S.
(
2011
)
Systemic cytokine response in moribund mice of streptococcal toxic shock syndrome model
.
Microb Pathog
 
50
:
109
113
.
Saksida
A.
Duh
D.
Wraber
B.
Dedushaj
I.
Ahmeti
S.
Avsic-Zupanc
T.
(
2010
)
Interacting roles of immune mechanisms and viral load in the pathogenesis of Crimean-Congo Hemorrhagic Fever
.
Clin Vaccine Immunol
 
17
:
1086
1093
.
Salvi
S.
Holgate
S.T.
(
1999
)
Could the airway epithelium play an important role in mucosal immunoglobulin A production?
Clin Exp Allergy
 
29
:
1597
1605
.
Santos Rocha
C.
Lakhdari
O.
Blottiere
H.M.
et al
. (
2011
)
Anti-inflammatory properties of dairy lactobacilli
.
Inflamm Bowel Dis
 
DOI: 10.1002/ibd.21834
.
Sbrogio-Almeida
M.E.
Mosca
T.
Massis
L.M.
Abrahamsohn
I.A.
Ferreira
L.C.
(
2004
)
Host and bacterial factors affecting induction of immune responses to flagellin expressed by attenuated Salmonella vaccine strains
.
Infect Immun
 
72
:
2546
2555
.
Schiffer
C.
Lalanne
A.I.
Cassard
L.
et al
. (
2011
)
A strain of Lactobacillus casei inhibits the effector phase of immune inflammation
.
J Immunol
 
187
:
2646
2655
.
Schreiner
M.
Liesenfeld
O.
(
2009
)
Small intestinal inflammation following oral infection with Toxoplasma gondii does not occur exclusively in C57BL/6 mice: review of 70 reports from the literature
.
Mem Inst Oswaldo Cruz
 
104
:
221
233
.
Sessa
R.
Di Pietro
M.
Schiavoni
G.
et al
. (
2009
)
Chlamydia pneumoniae induces T cell apoptosis through glutathione redox imbalance and secretion of TNF-alpha
.
Int J Immunopathol Pharmacol
 
22
:
659
668
.
Setiawan
T.
Metwali
A.
Blum
A.M.
Ince
M.N.
Urban
J.F.
Elliott
D.E.
Weinstock
J.V.
(
2007
)
Heligmosomoides polygyrus promotes regulatory T-Cell cytokine production in the murine normal distal intestine
.
Infect Immun
 
75
:
4655
4663
.
Sharma
M.
Rudel
T.
(
2009
)
Apoptosis resistance in Chlamydia-infected cells: a fate worse than death?
FEMS Immunol Med Microbiol
 
55
:
154
161
.
Sharma
S.
Sharma
M.
Bose
M.
(
2009
)
Mycobacterium tuberculosis infection of human monocyte-derived macrophages leads to apoptosis of T cells
.
Immunol Cell Biol
 
87
:
226
234
.
Shimada
K.
Crother
T.R.
Karlin
J.
et al
. (
2011
)
Caspase-1 dependent IL-1beta secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection
.
PLoS ONE
 
6
:
e21477
.
Sinsimer
D.
Fallows
D.
Peixoto
B.
Krahenbuhl
J.
Kaplan
G.
Manca
C.
(
2010
)
Mycobacterium leprae actively modulates the cytokine response in naive human monocytes
.
Infect Immun
 
78
:
293
300
.
Skeiky
YAW
Guderian
J.A.
Benson
D.R.
et al
. (
1995
)
A recombinant leishmania antigen that stimulates human peripheral-blood mononuclear-cells to express a Th1-type cytokine profile and to produce interleukin-12
.
J Exp Med
 
181
:
1527
1537
.
Skwor
T.A.
Atik
B.
Kandel
R.P.
Adhikari
H.K.
Sharma
B.
Dean
D.
(
2008
)
Role of secreted conjunctival mucosal cytokine and chemokine proteins in different stages of trachomatous disease
.
PLoS Negl Trop Dis
 
2
:
e264
.
Song
S.
Ling-Hu
H.
Roebuck
K.A.
Rabbi
M.F.
Donnelly
R.P.
Finnegan
A.
(
1997
)
Interleukin-10 inhibits interferon-gamma-induced intercellular adhesion molecule-1 gene transcription in human monocytes
.
Blood
 
89
:
4461
4469
.
Souza
C.D.
Evanson
O.A.
Weiss
D.J.
(
2008
)
Role of cell membrane receptors in the suppression of monocyte anti-microbial activity against Mycobacterium avium subsp paratuberculosis
.
Microb Pathog
 
44
:
215
223
.
Sprong
T.
Pickkers
P.
Geurts-Moespot
A.
et al
. (
2007
)
Macrophage migration inhibitory factor (MIF) in meningococcal septic shock and experimental human endotoxemia
.
Shock
 
27
:
482
487
.
Stabel
J.R.
Robbe-Austerman
S.
(
2011
)
Early immune markers associated with Mycobacterium avium subsp paratuberculosis infection in a neonatal calf model
.
Clin Vaccine Immunol
 
18
:
393
405
.
Stanford
M.M.
McFadden
G.
Karupiah
G.
Chaudhri
G.
(
2007
)
Immunopathogenesis of poxvirus infections: forecasting the impending storm
.
Immunol Cell Biol
 
85
:
93
102
.
Stapleton
A.E.
Au-Yeung
M.
Hooton
T.M.
et al
. (
2011
)
Randomized, placebo-controlled phase 2 trial of a Lactobacillus crispatus probiotic given intravaginally for prevention of recurrent urinary tract infection
.
Clin Infect Dis
 
52
:
1212
1217
.
Stijlemans
B.
Baral
T.N.
Guilliams
M.
et al
. (
2007
)
A glycosylphosphatidylinositol-based treatment alleviates trypanosomiasis-associated immunopathology
.
J Immunol
 
179
:
4003
4014
.
Strle
K.
Drouin
E.E.
Shen
S.Q.
et al
. (
2009
)
Borrelia burgdorferi stimulates macrophages to secrete higher levels of cytokines and chemokines than Borrelia afzelii or Borrelia garinii
.
J Infect Dis
 
200
:
1936
1943
.
Thiel
A.
Wu
P.H.
Lauster
R.
Braun
J.
Radbruch
A.
Sieper
J.
(
2000
)
Analysis of the antigen-specific T cell response in reactive arthritis by flow cytometry
.
Arthritis Rheum
 
43
:
2834
2842
.
Tsuji
M.
Suzuki
K.
Kinoshita
K.
Fagarasan
S.
(
2008
)
Dynamic interactions between bacteria and immune cells leading to intestinal IgA synthesis
.
Semin Immunol
 
20
:
59
66
.
Ulett
G.C.
Adderson
E.E.
(
2005
)
Nitric oxide is a key determinant of group B streptococcus-induced murine macrophage apoptosis
.
J Infect Dis
 
191
:
1761
1770
.
Ulett
G.C.
Adderson
E.E.
(
2006
)
Regulation of apoptosis by gram-positive bacteria: mechanistic diversity and consequences for immunity
.
Current Immunology Reviews
 
2
:
119
141
.
Ulett
G.C.
Ketheesan
N.
Hirst
R.G.
(
1998
)
Macrophage-lymphocyte interactions mediate anti-Burkholderia pseudomallei activity
.
FEMS Immunol Med Microbiol
 
21
:
283
286
.
Ulett
G.C.
Ketheesan
N.
Hirst
R.G.
(
2000
)
Cytokine gene expression in innately susceptible BALB/c mice and relatively resistant C57BL/6 mice during infection with virulent Burkholderia pseudomallei
.
Infect Immun
 
68
:
2034
2042
.
Ulett
G.C.
Labrooy
J.T.
Currie
B.J.
Barnes
J.L.
Ketheesan
N.
(
2005
)
A model of immunity to Burkholderia pseudomallei: unique responses following immunization and acute lethal infection
.
Microbes Infect
 
7
:
1263
1275
.
van der Poll
T.
Opal
S.M.
(
2008
)
Host-pathogen interactions in sepsis
.
Lancet Infect Dis
 
8
:
32
43
.
Vanham
G.
Penne
L.
Allemeersch
H.
et al
. (
2000
)
Modeling HIV transfer between dendritic cells and T cells: importance of HIV phenotype, dendritic cell-T cell contact and T-cell activation
.
AIDS
 
14
:
2299
2311
.
Vardhan
H.
Bhengraj
A.R.
Jha
R.
Srivastava
P.
Jha
H.C.
Mittal
A.
(
2010
)
Higher expression of ferritin protects Chlamydia trachomatis infected HeLa 229 cells from reactive oxygen species mediated cell death
.
Biochem Cell Biol
 
88
:
835
842
.
Vargas-Inchaustegui
D.A.
Hogg
A.E.
Tulliano
G.
Llanos-Cuentas
A.
Arevalo
J.
Endsley
J.J.
Soong
L.
(
2010
)
CXCL10 production by human monocytes in response to Leishmania braziliensis infection
.
Infect Immun
 
78
:
301
308
.
Vats
V.
Agrawal
T.
Salhan
S.
Mittal
A.
(
2007
)
Primary and secondary immune responses of mucosal and peripheral lymphocytes during Chlamydia trachomatis infection
.
FEMS Immunol Med Microbiol
 
49
:
280
287
.
Vernel-Pauillac
F.
Goarant
C.
(
2010
)
Differential cytokine gene expression according to outcome in a hamster model of leptospirosis
.
PLoS Negl Trop Dis
 
4
:
e582
.
Vieira
P.
De waal malefyt
R.
Dang
M.N.
et al
. (
1991
)
Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones — homology to Epstein–Barr-Virus open reading frame BCRFI
.
P Natl Acad Sci USA
 
88
:
1172
1176
.
Villena
J.
Barbieri
N.
Salva
S.
Herrera
M.
Alvarez
S.
(
2009
)
Enhanced immune response to pneumococcal infection in malnourished mice nasally treated with heat-killed Lactobacillus casei
.
Microbiol Immunol
 
53
:
636
646
.
Wang
P.
Wu
P.
Siegel
M.I.
Egan
R.W.
Billah
M.M.
(
1994
)
IL-10 inhibits transcription of cytokine genes in human peripheral blood mononuclear cells
.
J Immunol
 
153
:
811
816
.
Wang
P.
Wu
P.
Siegel
M.I.
Egan
R.W.
Billah
M.M.
(
1995
)
Interleukin (IL)-10 inhibits nuclear factor kappa B (NF kappa B) activation in human monocytes. IL-10 and IL-4 suppress cytokine synthesis by different mechanisms
.
J Biol Chem
 
270
:
9558
9563
.
Wang
S.M.
Lu
I.H.
Lin
Y.L.
et al
. (
2008
)
The severity of Streptococcus pyogenes infections in children is significantly associated with plasma levels of inflammatory cytokines
.
Diagn Microbiol Infect Dis
 
61
:
165
169
.
Waters
A.
Hassan
J.
Degascun
C.
et al
. (
2010
)
Human Cytomegalovirus UL144 is associated with viremia and infant development sequelae in congenital infection
.
J Clin Microbiol
 
48
:
3956
3962
.
Wauquier
N.
Becquart
P.
Nkoghe
D.
Padilla
C.
Ndjoyi-Mbiguino
A.
Leroy
E.M.
(
2011
)
The acute phase of Chikungunya Virus infection in humans is associated with strong innate immunity and T CD8 Cell activation
.
J Infect Dis
 
204
:
115
123
.
Weiss
D.J.
Evanson
O.A.
de Souza
C.
Abrahamsen
M.S.
(
2005
)
A critical role of interleukin-10 in the response of bovine macrophages to infection by Mycobacterium avium subsp paratuberculosis
.
Am J Vet Res
 
66
:
721
726
.
Weiss
G.
Rasmussen
S.
Zeuthen
L.H.
Nielsen
B.N.
Jarmer
H.
Jespersen
L.
Frokiaer
H.
(
2010
)
Lactobacillus acidophilus induces virus immune defence genes in murine dendritic cells by a Toll-like receptor-2-dependent mechanism
.
Immunology
 
131
:
268
281
.
West
N.P.
Pyne
D.B.
Cripps
A.W.
et al
. (
2011
)
Lactobacillus fermentum (PCC(R)) supplementation and gastrointestinal and respiratory-tract illness symptoms: a randomised control trial in athletes
.
Nutr J
 
10
:
30
.
Williams
N.L.
Morris
J.L.
Rush
C.
Govan
B.L.
Ketheesan
N.
(
2011
)
Impact of streptozotocin-induced diabetes on functional responses of dendritic cells and macrophages towards Burkholderia pseudomallei
.
FEMS Immunol Med Microbiol
 
61
:
218
227
.
Wingate
P.J.
McAulay
K.A.
Anthony
I.C.
Crawford
D.H.
(
2009
)
Regulatory T cell activity in primary and persistent Epstein–Barr virus infection
.
J Med Virol
 
81
:
870
877
.
Woof
J.M.
Kerr
M.A.
(
2006
)
The function of immunoglobulin A in immunity
.
J Pathol
 
208
:
270
282
.
Wu
K.
Bi
Y.T.
Sun
K.
Wang
C.Z.
(
2007
)
IL-10-producing type 1 regulatory T cells and allergy
.
Cell Mol Immunol
 
4
:
269
275
.
Wyant
T.L.
Tanner
M.K.
Sztein
M.B.
(
1999
)
Salmonella typhi flagella are potent inducers of proinflammatory cytokine secretion by human monocytes
.
Infect Immun
 
67
:
3619
3624
.
Xin
L.J.
Li
Y.G.
Soong
L.
(
2007
)
Role of interleukin-1 beta in activating the CD11c(high) CD45RBD(−) dendritic cell subset and priming Leishmania amazonensis specific CD4(+) T cells in vitro and in vivo
.
Infect Immun
 
75
:
5018
5026
.
Yang
X.
Gartner
J.
Zhu
L.H.
Wang
S.H.
Brunham
R.C.
(
1999
)
IL-10 gene knockout mice show enhanced Th1-like protective immunity and absent granuloma formation following Chlamydia trachomatis lung infection
.
J Immunol
 
162
:
1010
1017
.
Yang
J.H.
Zhao
J.Q.
Yang
Y.F.
et al
. (
2007
)
Schistosoma japonicum egg antigens stimulate CD4(+) CD25(+) T cells and modulate airway inflammation in a murine model of asthma
.
Immunology
 
120
:
8
18
.
Yaraei
K.
Campbell
L.A.
Zhu
X.
Liles
W.C.
Kuo
C.C.
Rosenfeld
M.E.
(
2005
)
Chlamydia pneumoniae augments the oxidized low-density lipoprotein-induced death of mouse macrophages by a caspase-independent pathway
.
Infect Immun
 
73
:
4315
4322
.
Yin
Z.H.
Braun
J.
Neure
L.
Wu
P.H.
Liu
L.Z.
Eggens
U.
Sieper
J.
(
1997
)
Crucial role of interleukin-10/interleukin-12 balance in the regulation of the type 2 T helper cytokine response in reactive arthritis
.
Arthritis Rheum
 
40
:
1788
1797
.
Zheng
W.
Wang
Q.H.
Feng
H.
Liu
J.
Meng
H.R.
Cao
Y.M.
(
2009
)
CD4(+)CD25(+)Foxp3(+) regulatory T cells prevent the development of Th1 immune response by inhibition of dendritic cell function during the early stage of Plasmodium yoelii infection in susceptible BALB/c mice
.
Folia Parasitol
 
56
:
242
250
.
Zhou
L.
Nazarian
A.A.
Smale
S.T.
(
2004
)
Interleukin-10 inhibits interleukin-12 p40 gene transcription by targeting a late event in the activation pathway
.
Mol Cell Biol
 
24
:
2385
2396
.

Author notes

Editor: Peter Timms