The regulation of IL-10 production by immune cells (original) (raw)
Hawrylowicz, C. M. & O'Garra, A. Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma. Nature Rev. Immunol.5, 271–283 (2005). ArticleCAS Google Scholar
O'Garra, A., Barrat, F. J., Castro, A. G., Vicari, A. & Hawrylowicz, C. Strategies for use of IL-10 or its antagonists in human disease. Immunol. Rev.223, 114–131 (2008). This review covers the most recent advances in the use of IL-10 in human disease, from immune-mediated diseases to cancer. ArticleCASPubMed Google Scholar
Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol.19, 683–765 (2001). ArticleCASPubMed Google Scholar
Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell75, 263–274 (1993). This is the first report showing the important role of IL-10 in regulating the immune response and it suggests that the absence of IL-10 is associated with gut inflammation. ArticleCASPubMed Google Scholar
Sellon, R. K. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun.66, 5224–5231 (1998). CASPubMedPubMed Central Google Scholar
Brooks, D. G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nature Med.12, 1301–1309 (2006). ArticleCASPubMed Google Scholar
Gazzinelli, R. T. et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J. Immunol.157, 798–805 (1996). CASPubMed Google Scholar
Li, C., Corraliza, I. & Langhorne, J. A defect in interleukin-10 leads to enhanced malarial disease in Plasmodium chabaudi chabaudi infection in mice. Infect. Immun.67, 4435–4442 (1999). CASPubMedPubMed Central Google Scholar
O'Garra, A. & Vieira, P. TH1 cells control themselves by producing interleukin-10. Nature Rev. Immunol.7, 425–428 (2007). ArticleCAS Google Scholar
Fiorentino, D. F., Bond, M. W. & Mosmann, T. R. 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 (1989). ArticleCASPubMed Google Scholar
O'Garra, A. & Vieira, P. Regulatory T cells and mechanisms of immune system control. Nature Med.10, 801–805 (2004). ArticleCASPubMed Google Scholar
Roncarolo, M. G. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev.212, 28–50 (2006). ArticleCASPubMed Google Scholar
Maynard, C. L. & Weaver, C. T. Diversity in the contribution of interleukin-10 to T-cell-mediated immune regulation. Immunol. Rev.226, 219–233 (2008). ArticleCASPubMedPubMed Central Google Scholar
Maloy, K. J. & Powrie, F. Regulatory T cells in the control of immune pathology. Nature Immunol.2, 816–822 (2001). ArticleCAS Google Scholar
Hoffmann, K. F., Cheever, A. W. & Wynn, T. A. IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J. Immunol.164, 6406–6416 (2000). ArticleCASPubMed Google Scholar
Grunig, G. et al. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J. Exp. Med.185, 1089–1099 (1997). ArticleCASPubMedPubMed Central Google Scholar
Zuany-Amorim, C. et al. Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice. J. Clin. Invest.95, 2644–2651 (1995). ArticleCASPubMedPubMed Central Google Scholar
Murray, P. J. Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr. Opin. Pharmacol.6, 379–386 (2006). ArticleCASPubMed Google Scholar
Barrat, F. J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med.195, 603–616 (2002). ArticleCASPubMedPubMed Central Google Scholar
Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature449, 819–826 (2007). ArticleCASPubMed Google Scholar
Fiorentino, D. F., Zlotnik, A., Mosmann, T. R., Howard, M. & O'Garra, A. IL-10 inhibits cytokine production by activated macrophages. J. Immunol.147, 3815–3822 (1991). This study shows for the first time that IL-10 can block an immune response by suppressing cytokine production by mouse macrophages, suggesting that these cells are targets for IL-10 function. CASPubMed Google Scholar
de Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G. & de Vries, J. E. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med.174, 1209–1220 (1991). This study shows for the first time that IL-10 can block an immune response by suppressing cytokine production by human monocytes, thereby positioning these cells as targets for IL-10 function. ArticleCASPubMed Google Scholar
Gerber, J. S. & Mosser, D. M. Reversing lipopolysaccharide toxicity by ligating the macrophage Fcγ receptors. J. Immunol.166, 6861–6868 (2001). ArticleCASPubMed Google Scholar
Boonstra, A. et al. Macrophages and myeloid dendritic cells, but not plasmacytoid dendritic cells, produce IL-10 in response to MyD88- and TRIF-dependent TLR signals, and TLR-independent signals. J. Immunol.177, 7551–7558 (2006). ArticleCASPubMed Google Scholar
Chang, E. Y., Guo, B., Doyle, S. E. & Cheng, G. Cutting edge: involvement of the type I IFN production and signaling pathway in lipopolysaccharide-induced IL-10 production. J. Immunol.178, 6705–6709 (2007). ArticleCASPubMed Google Scholar
Edwards, A. D. et al. Microbial recognition via Toll-like receptor-dependent and -independent pathways determines the cytokine response of murine dendritic cell subsets to CD40 triggering. J. Immunol.169, 3652–3660 (2002). ArticleCASPubMed Google Scholar
Agrawal, S. et al. Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J. Immunol.171, 4984–4989 (2003). ArticleCASPubMed Google Scholar
Dillon, S. et al. A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J. Immunol.172, 4733–4743 (2004). ArticleCASPubMed Google Scholar
McGuirk, P., McCann, C. & Mills, K. H. 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 (2002). ArticleCASPubMedPubMed Central Google Scholar
Rogers, N. C. et al. Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity22, 507–517 (2005). ArticleCASPubMed Google Scholar
Akbari, O., DeKruyff, R. H. & Umetsu, D. T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nature Immunol.2, 725–731 (2001). ArticleCAS Google Scholar
Siewe, L. et al. Interleukin-10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA. Eur. J. Immunol.36, 3248–3255 (2006). ArticleCASPubMed Google Scholar
Zhang, X., Majlessi, L., Deriaud, E., Leclerc, C. & Lo-Man, R. Coactivation of Syk kinase and MyD88 adaptor protein pathways by bacteria promotes regulatory properties of neutrophils. Immunity31, 761–771 (2009). ArticleCASPubMed Google Scholar
Netea, M. G. et al. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J. Immunol.172, 3712–3718 (2004). ArticleCASPubMed Google Scholar
Hu, X. et al. IFN-γ suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity24, 563–574 (2006). This study provides the first molecular basis for the negative feedback loops that regulate IL-10 expression. ArticleCASPubMed Google Scholar
Jang, S., Uematsu, S., Akira, S. & Salgame, P. IL-6 and IL-10 induction from dendritic cells in response to Mycobacterium tuberculosis is predominantly dependent on TLR2-mediated recognition. J. Immunol.173, 3392–3397 (2004). ArticleCASPubMed Google Scholar
Sing, A. et al. Yersinia V-antigen exploits Toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression. J. Exp. Med.196, 1017–1024 (2002). ArticleCASPubMedPubMed Central Google Scholar
Moreira, L. O. et al. 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 (2008). ArticleCASPubMedPubMed Central Google Scholar
Hacker, H. et al. Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature439, 204–207 (2006). ArticlePubMedCAS Google Scholar
Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol.4, 499–511 (2004). ArticleCAS Google Scholar
Symons, A., Beinke, S. & Ley, S. C. MAP kinase kinase kinases and innate immunity. Trends Immunol.27, 40–48 (2006). ArticleCASPubMed Google Scholar
Yi, A. K. et al. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J. Immunol.168, 4711–4720 (2002). ArticleCASPubMed Google Scholar
Agrawal, A., Dillon, S., Denning, T. L. & Pulendran, B. ERK1−/− mice exhibit Th1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis. J. Immunol.176, 5788–5796 (2006). ArticleCASPubMed Google Scholar
Kaiser, F. et al. TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells. J. Exp. Med.206, 1863–1871 (2009). ArticleCASPubMedPubMed Central Google Scholar
Banerjee, A., Gugasyan, R., McMahon, M. & Gerondakis, S. Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. Proc. Natl Acad. Sci. USA103, 3274–3279 (2006). ArticleCASPubMedPubMed Central Google Scholar
Kanters, E. et al. Inhibition of NF-κB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest.112, 1176–1185 (2003). ArticleCASPubMedPubMed Central Google Scholar
Saraiva, M. et al. Identification of a macrophage-specific chromatin signature in the IL-10 locus. J. Immunol.175, 1041–1046 (2005). ArticleCASPubMed Google Scholar
Gringhuis, S. I. et al. C-type lectin DC-SIGN modulates Toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-κB. Immunity26, 605–616 (2007). ArticleCASPubMed Google Scholar
Gantner, B. N., Simmons, R. M., Canavera, S. J., Akira, S. & Underhill, D. M. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J. Exp. Med.197, 1107–1117 (2003). ArticleCASPubMedPubMed Central Google Scholar
Slack, E. C. et al. Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimulated with zymosan. Eur. J. Immunol.37, 1600–1612 (2007). ArticleCASPubMed Google Scholar
Lucas, M., Zhang, X., Prasanna, V. & Mosser, D. M. ERK activation following macrophage FcγR ligation leads to chromatin modifications at the IL-10 locus. J. Immunol.175, 469–477 (2005). ArticleCASPubMed Google Scholar
Ma, W. et al. The p38 mitogen-activated kinase pathway regulates the human interleukin-10 promoter via the activation of Sp1 transcription factor in lipopolysaccharide-stimulated human macrophages. J. Biol. Chem.276, 13664–13674 (2001). ArticleCASPubMed Google Scholar
Kim, C. et al. The kinase p38α serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nature Immunol.9, 1019–1027 (2008). ArticleCAS Google Scholar
Park, J. M. et al. Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis — CREB and NF-κB as key regulators. Immunity23, 319–329 (2005). CASPubMed Google Scholar
Jarnicki, A. G. et al. Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J. Immunol.180, 3797–3806 (2008). ArticleCASPubMed Google Scholar
Foey, A. D. et al. Regulation of monocyte IL-10 synthesis by endogenous IL-1 and TNF-α: role of the p38 and p42/44 mitogen-activated protein kinases. J. Immunol.160, 920–928 (1998). CASPubMed Google Scholar
Chi, H. et al. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc. Natl Acad. Sci. USA103, 2274–2279 (2006). ArticleCASPubMedPubMed Central Google Scholar
Zhao, Q. et al. MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock. J. Exp. Med.203, 131–140 (2006). ArticleCASPubMedPubMed Central Google Scholar
Hammer, M. et al. Dual specificity phosphatase 1 (DUSP1) regulates a subset of LPS-induced genes and protects mice from lethal endotoxin shock. J. Exp. Med.203, 15–20 (2006). References 61–63 identify the p38 regulator DUSP1 as a negative regulator of IL-10 expression, providing evidence that prolonged p38 activation leads to stronger IL-10 transcription. ArticleCASPubMedPubMed Central Google Scholar
Ananieva, O. et al. The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nature Immunol.9, 1028–1036 (2008). This study shows that activation of MSK1 and MSK2 by p38 and ERK leads to enhanced IL-10 expression by macrophages and limits the production of pro-inflammatory cytokines. ArticleCAS Google Scholar
Hammer, M. et al. Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10. Eur. J. Immunol.35, 2991–3001 (2005). ArticleCASPubMed Google Scholar
Lang, R., Patel, D., Morris, J. J., Rutschman, R. L. & Murray, P. J. Shaping gene expression in activated and resting primary macrophages by IL-10. J. Immunol.169, 2253–2263 (2002). ArticleCASPubMed Google Scholar
Staples, K. J. et al. IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3. J. Immunol.178, 4779–4785 (2007). ArticleCASPubMed Google Scholar
Moore, K. W. et al. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein–Barr virus gene BCRFI. Science248, 1230–1234 (1990). ArticleCASPubMed Google Scholar
Jankovic, D. et al. Conventional T-bet+Foxp3− Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med.204, 273–283 (2007). ArticleCASPubMedPubMed Central Google Scholar
Anderson, C. F., Oukka, M., Kuchroo, V. J. & Sacks, D. CD4+CD25−Foxp3− Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med.204, 285–297 (2007). References 69 and 70 demonstrate the existence of IL-10-producing TH1 cells and their relevance duringin vivoinfections. ArticleCASPubMedPubMed Central Google Scholar
Gabrysova, L. et al. Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10-secreting Th1 cells. J. Exp. Med.206, 1755–1767 (2009). ArticleCASPubMedPubMed Central Google Scholar
Saraiva, M. et al. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity31, 209–219 (2009). This study provides the first molecular description of the pathways that regulate IL-10 expression by TH1, TH2 and TH17 cells, placing ERK, and possibly MAF, as components of a common pathway for IL-10 induction by T cells. ArticleCASPubMedPubMed Central Google Scholar
Gerosa, F. et al. CD4+ T cell clones producing both interferon-γ and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin. Immunol.92, 224–234 (1999). ArticleCASPubMed Google Scholar
Meyaard, L., Hovenkamp, E., Otto, S. A. & Miedema, F. IL-12-induced IL-10 production by human T cells as a negative feedback for IL-12-induced immune responses. J. Immunol.156, 2776–2782 (1996). CASPubMed Google Scholar
Yssel, H. et al. IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells. J. Immunol.149, 2378–2384 (1992). CASPubMed Google Scholar
Del Prete, G. et al. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J. Immunol.150, 353–360 (1993). CASPubMed Google Scholar
McGeachy, M. J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nature Immunol.8, 1390–1397 (2007). ArticleCAS Google Scholar
Fitzgerald, D. C. et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nature Immunol.8, 1372–1379 (2007). ArticleCAS Google Scholar
Stumhofer, J. S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nature Immunol.8, 1363–1371 (2007). ArticleCAS Google Scholar
Veldhoen, M. et al. Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immunol.9, 1341–1346 (2008). ArticleCAS Google Scholar
Zhu, J. et al. Conditional deletion of Gata3 shows its essential function in TH1–TH2 responses. Nature Immunol.5, 1157–1165 (2004). ArticleCAS Google Scholar
Shoemaker, J., Saraiva, M. & O'Garra, A. GATA-3 directly remodels the IL-10 locus independently of IL-4 in CD4+ T cells. J. Immunol.176, 3470–3479 (2006). This study describes a new role for GATA3, showing that in addition to being the master regulator of TH2 cell differentiation, GATA3 also controls the remodelling of theIl10locus in TH2 cells. ArticleCASPubMed Google Scholar
Chang, H. D. et al. Expression of IL-10 in Th memory lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3. Eur. J. Immunol.37, 807–817 (2007). ArticleCASPubMed Google Scholar
Xu, J. et al. c-Maf regulates IL-10 expression during Th17 polarization. J. Immunol.182, 6226–6236 (2009). This study provides evidence that MAF is a key transcription factor for IL-10 expression by TH17 cells and that MAF is not a TH2 cell-specific transcription factor. ArticleCASPubMed Google Scholar
Spolski, R., Kim, H. P., Zhu, W., Levy, D. E. & Leonard, W. J. IL-21 mediates suppressive effects via its induction of IL-10. J. Immunol.182, 2859–2867 (2009). ArticleCASPubMed Google Scholar
Batten, M. et al. Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells. J. Immunol.180, 2752–2756 (2008). ArticleCASPubMed Google Scholar
Pot, C. et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J. Immunol.183, 797–801 (2009). In addition to reference 85, this study supports the role of MAF as a key transcription factor for IL-10 expression in T cells, providing some insights on the molecular pathways that link MAF to IL-10 expression. ArticleCASPubMed Google Scholar
Kalliolias, G. D. & Ivashkiv, L. B. IL-27 activates human monocytes via STAT1 and suppresses IL-10 production but the inflammatory functions of IL-27 are abrogated by TLRs and p38. J. Immunol.180, 6325–6333 (2008). ArticleCASPubMed Google Scholar
Fuqua, C. F., Akomeah, R., Price, J. O. & Adunyah, S. E. Involvement of ERK-1/2 in IL-21-induced cytokine production in leukemia cells and human monocytes. Cytokine44, 101–107 (2008). ArticleCASPubMedPubMed Central Google Scholar
Owaki, T., Asakawa, M., Fukai, F., Mizuguchi, J. & Yoshimoto, T. IL-27 induces Th1 differentiation via p38 MAPK/T-bet- and intercellular adhesion molecule-1/LFA-1/ERK1/2-dependent pathways. J. Immunol.177, 7579–7587 (2006). ArticleCASPubMed Google Scholar
Maynard, C. L. et al. Contrasting roles for all-trans retinoic acid in TGF-β-mediated induction of Foxp3 and Il10 genes in developing regulatory T cells. J. Exp. Med.206, 343–357 (2009). This study provides molecular evidence for the regulation of IL-10 expression by TRegcells. ArticleCASPubMedPubMed Central Google Scholar
Haringer, B., Lozza, L., Steckel, B. & Geginat, J. Identification and characterization of IL-10/IFN-γ-producing effector-like T cells with regulatory function in human blood. J. Exp. Med.206, 1009–1017 (2009). ArticlePubMedCASPubMed Central Google Scholar
Rivino, L. et al. CCR6 is expressed on an IL-10-producing, auto-reactive memory T cell subset with context-dependent regulatory function. J. Exp. Med. (in the press).
Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science299, 1057–1061 (2003). ArticleCASPubMed Google Scholar
Vieira, P. L. et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J. Immunol.172, 5986–5993 (2004). ArticleCASPubMed Google Scholar
Maynard, C. L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10. Nature Immunol.8, 931–941 (2007). ArticleCAS Google Scholar
Belkaid, Y. Regulatory T cells and infection: a dangerous necessity. Nature Rev. Immunol.7, 875–888 (2007). ArticleCAS Google Scholar
Shevach, E. M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity30, 636–645 (2009). ArticleCASPubMed Google Scholar
Barthlott, T. et al. CD25+ CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production. Int. Immunol.17, 279–288 (2005). ArticleCASPubMed Google Scholar
de la Rosa, M., Rutz, S., Dorninger, H. & Scheffold, A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol.34, 2480–2488 (2004). ArticleCASPubMed Google Scholar
Sundstedt, A., O'Neill, E. J., Nicolson, K. S. & Wraith, D. C. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J. Immunol.170, 1240–1248 (2003). ArticleCASPubMed Google Scholar
Mills, K. H. & McGuirk, P. Antigen-specific regulatory T cells — their induction and role in infection. Semin. Immunol.16, 107–117 (2004). ArticleCASPubMed Google Scholar
Akbari, O. et al. Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nature Med.8, 1024–1032 (2002). ArticleCASPubMed Google Scholar
Ito, T. et al. Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J. Exp. Med.204, 105–115 (2007). ArticleCASPubMedPubMed Central Google Scholar
Witsch, E. J. et al. ICOS and CD28 reversely regulate IL-10 on re-activation of human effector T cells with mature dendritic cells. Eur. J. Immunol.32, 2680–2686 (2002). ArticleCASPubMed Google Scholar
Lohning, M. et al. Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J. Exp. Med.197, 181–193 (2003). ArticleCASPubMedPubMed Central Google Scholar
Salgame, P. et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science254, 279–282 (1991). ArticleCASPubMed Google Scholar
Tanchot, C. et al. Modifications of CD8+ T cell function during in vivo memory or tolerance induction. Immunity8, 581–590 (1998). ArticleCASPubMed Google Scholar
Gilliet, M. & Liu, Y. J. Generation of human CD8 T regulatory cells by CD40 ligand-activated plasmacytoid dendritic cells. J. Exp. Med.195, 695–704 (2002). ArticleCASPubMedPubMed Central Google Scholar
O'Garra, A. et al. Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur. J. Immunol.22, 711–717 (1992). ArticleCASPubMed Google Scholar
Burdin, N., Rousset, F. & Banchereau, J. B-cell-derived IL-10: production and function. Methods11, 98–111 (1997). ArticleCASPubMed Google Scholar
Mauri, C., Gray, D., Mushtaq, N. & Londei, M. Prevention of arthritis by interleukin 10-producing B cells. J. Exp. Med.197, 489–501 (2003). ArticleCASPubMedPubMed Central Google Scholar
Fillatreau, S., Sweenie, C. H., McGeachy, M. J., Gray, D. & Anderton, S. M. B cells regulate autoimmunity by provision of IL-10. Nature Immunol.3, 944–950 (2002). ArticleCAS Google Scholar
Sun, C. M., Deriaud, E., Leclerc, C. & Lo-Man, R. Upon TLR9 signaling, CD5+ B cells control the IL-12-dependent Th1-priming capacity of neonatal DCs. Immunity22, 467–477 (2005). ArticleCASPubMed Google Scholar
Heine, G. et al. 1, 25-dihydroxyvitamin D3 promotes IL-10 production in human B cells. Eur. J. Immunol.38, 2210–2218 (2008). ArticleCASPubMed Google Scholar
Grimbaldeston, M. A., Nakae, S., Kalesnikoff, J., Tsai, M. & Galli, S. J. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nature Immunol.8, 1095–1104 (2007). ArticleCAS Google Scholar
Masuda, A., Yoshikai, Y., Aiba, K. & Matsuguchi, T. Th2 cytokine production from mast cells is directly induced by lipopolysaccharide and distinctly regulated by c-Jun N-terminal kinase and p38 pathways. J. Immunol.169, 3801–3810 (2002). ArticleCASPubMed Google Scholar
Brightbill, H. D., Plevy, S. E., Modlin, R. L. & Smale, S. T. A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. J. Immunol.164, 1940–1951 (2000). ArticleCASPubMed Google Scholar
Tone, M., Powell, M. J., Tone, Y., Thompson, S. A. & Waldmann, H. IL-10 gene expression is controlled by the transcription factors Sp1 and Sp3. J. Immunol.165, 286–291 (2000). ArticleCASPubMed Google Scholar
Brenner, S. et al. cAMP-induced interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and monocytic differentiation. J. Biol. Chem.278, 5597–5604 (2003). ArticleCASPubMed Google Scholar
Liu, Y. W., Tseng, H. P., Chen, L. C., Chen, B. K. & Chang, W. C. Functional cooperation of simian virus 40 promoter factor 1 and CCAAT/enhancer-binding protein β and δ in lipopolysaccharide-induced gene activation of IL-10 in mouse macrophages. J. Immunol.171, 821–828 (2003). ArticleCASPubMed Google Scholar
Ziegler-Heitbrock, L. et al. IFN-α induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3. J. Immunol.171, 285–290 (2003). ArticleCASPubMed Google Scholar
Mori, N. & Prager, D. Activation of the interleukin-10 gene in the human T lymphoma line HuT 78: identification and characterization of NF-κB binding sites in the regulatory region of the interleukin-10 gene. Eur. J. Haematol.59, 162–170 (1997). ArticleCASPubMed Google Scholar
Cao, S., Zhang, X., Edwards, J. P. & Mosser, D. M. NF-κB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages. J. Biol. Chem.281, 26041–26050 (2006). ArticleCASPubMed Google Scholar
Chakrabarti, A. et al. Protein kinase R-dependent regulation of interleukin-10 in response to double-stranded RNA. J. Biol. Chem.283, 25132–25139 (2008). ArticleCASPubMedPubMed Central Google Scholar
Csoka, B. et al. A2A adenosine receptors and C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli. Blood110, 2685–2695 (2007). ArticleCASPubMedPubMed Central Google Scholar
Chung, E. Y. et al. Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1. Immunity27, 952–964 (2007). ArticleCASPubMedPubMed Central Google Scholar
Kitani, A. et al. Transforming growth factor (TGF)-β1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-β1-mediated fibrosis. J. Exp. Med.198, 1179–1188 (2003). ArticleCASPubMedPubMed Central Google Scholar
Kim, J. I., Ho, I. C., Grusby, M. J. & Glimcher, L. H. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity10, 745–751 (1999). ArticleCASPubMed Google Scholar
Cao, S., Liu, J., Song, L. & Ma, X. The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages. J. Immunol.174, 3484–3492 (2005). ArticleCASPubMed Google Scholar
Wang, Z. Y. et al. Regulation of IL-10 gene expression in Th2 cells by Jun proteins. J. Immunol.174, 2098–2105 (2005). ArticleCASPubMed Google Scholar
Jones, E. A. & Flavell, R. A. Distal enhancer elements transcribe intergenic RNA in the IL-10 family gene cluster. J. Immunol.175, 7437–7446 (2005). ArticleCASPubMed Google Scholar
Im, S. H., Hueber, A., Monticelli, S., Kang, K. H. & Rao, A. Chromatin-level regulation of the IL10 gene in T cells. J. Biol. Chem.279, 46818–46825 (2004). ArticleCASPubMed Google Scholar
Grenningloh, R., Kang, B. Y. & Ho, I. C. Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses. J. Exp. Med.201, 615–626 (2005). ArticleCASPubMedPubMed Central Google Scholar
Sullivan, B. M. et al. Increased susceptibility of mice lacking T-bet to infection with Mycobacterium tuberculosis correlates with increased IL-10 and decreased IFN-γ production. J. Immunol.175, 4593–4602 (2005). ArticleCASPubMed Google Scholar
Yee, C. S. et al. Enhanced production of IL-10 by dendritic cells deficient in CIITA. J. Immunol.174, 1222–1229 (2005). ArticleCASPubMed Google Scholar
VanDeusen, J. B. et al. STAT-1-mediated repression of monocyte interleukin-10 gene expression in vivo. Eur. J. Immunol.36, 623–630 (2006). ArticleCASPubMed Google Scholar
Riemann, M., Endres, R., Liptay, S., Pfeffer, K. & Schmid, R. M. The IκB protein Bcl-3 negatively regulates transcription of the IL-10 gene in macrophages. J. Immunol.175, 3560–3568 (2005). ArticleCASPubMed Google Scholar
Kusam, S., Toney, L. M., Sato, H. & Dent, A. L. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J. Immunol.170, 2435–2441 (2003). ArticleCASPubMed Google Scholar
Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science325, 1006–1010 (2009). ArticleCASPubMedPubMed Central Google Scholar
Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity31, 457–468 (2009). ArticleCASPubMed Google Scholar
Anderson, P. Post-transcriptional control of cytokine production. Nature Immunol.9, 353–359 (2008). ArticleCAS Google Scholar
Powell, M. J., Thompson, S. A., Tone, Y., Waldmann, H. & Tone, M. Posttranscriptional regulation of IL-10 gene expression through sequences in the 3′-untranslated region. J. Immunol.165, 292–296 (2000). ArticleCASPubMed Google Scholar
Brown, C. Y., Lagnado, C. A., Vadas, M. A. & Goodall, G. J. Differential regulation of the stability of cytokine mRNAs in lipopolysaccharide-activated blood monocytes in response to interleukin-10. J. Biol. Chem.271, 20108–20112 (1996). ArticleCASPubMed Google Scholar
Kishore, R., Tebo, J. M., Kolosov, M. & Hamilton, T. A. Cutting edge: clustered AU-rich elements are the target of IL-10-mediated mRNA destabilization in mouse macrophages. J. Immunol.162, 2457–2461 (1999). CASPubMed Google Scholar
Nemeth, Z. H. et al. Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism. J. Immunol.175, 8260–8270 (2005). ArticleCASPubMed Google Scholar
Stoecklin, G. et al. Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin. J. Biol. Chem.283, 11689–11699 (2008). ArticleCASPubMedPubMed Central Google Scholar
Tudor, C. et al. The p38 MAPK pathway inhibits tristetraprolin-directed decay of interleukin-10 and pro-inflammatory mediator mRNAs in murine macrophages. FEBS Lett.583, 1933–1938 (2009). ArticleCASPubMedPubMed Central Google Scholar
Schaljo, B. et al. Tristetraprolin is required for full anti-inflammatory response of murine macrophages to IL-10. J. Immunol.183, 1197–1206 (2009). ArticleCASPubMed Google Scholar
Sharma, A. et al. Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proc. Natl Acad. Sci. USA106, 5761–5766 (2009). ArticleCASPubMedPubMed Central Google Scholar
Izcue, A., Coombes, J. L. & Powrie, F. Regulatory lymphocytes and intestinal inflammation. Annu. Rev. Immunol.27, 313–338 (2009). ArticleCASPubMed Google Scholar
Spencer, S. D. et al. The orphan receptor CRF2–4 is an essential subunit of the interleukin 10 receptor. J. Exp. Med.187, 571–578 (1998). ArticleCASPubMedPubMed Central Google Scholar
Roers, A. et al. T cell-specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J. Exp. Med.200, 1289–1297 (2004). ArticleCASPubMedPubMed Central Google Scholar
Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature389, 737–742 (1997). ArticleCASPubMed Google Scholar
Asseman, C., Read, S. & Powrie, F. Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J. Immunol.171, 971–978 (2003). ArticleCASPubMed Google Scholar
Van Montfrans, C. et al. Prevention of colitis by interleukin 10-transduced T lymphocytes in the SCID mice transfer model. Gastroenterology123, 1865–1876 (2002). ArticleCASPubMed Google Scholar
Davidson, N. J. et al. T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. J. Exp. Med.184, 241–251 (1996). ArticleCASPubMed Google Scholar
Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nature Genet.40, 1319–1323 (2008). ArticleCASPubMed Google Scholar
Noguchi, E., Homma, Y., Kang, X., Netea, M. G. & Ma, X. A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nature Immunol.10, 471–479 (2009). ArticleCAS Google Scholar
Coombes, J. L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med.204, 1757–1764 (2007). ArticleCASPubMedPubMed Central Google Scholar
Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med.204, 1765–1774 (2007). ArticleCASPubMedPubMed Central Google Scholar
Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med.204, 1775–1785 (2007). ArticleCASPubMedPubMed Central Google Scholar
Zhang, X., Edwards, J. P. & Mosser, D. M. Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription. J. Immunol.177, 1282–1288 (2006). ArticleCASPubMed Google Scholar
Villagra, A. et al. The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nature Immunol.10, 92–100 (2009). ArticleCAS Google Scholar