Turning on and off the Immunological Switch: Immune Response Polarization and Its Control by IL-10 and STAT3



The innate and immunologic arms of host resistance to pathogenic infections use distinct patterns of cytokine production to direct appropriate tissue responses. This chapter discusses how this “Immunological Switch” is coordinated by distinct T helper cell lineages and how IL-10 and STAT3 signaling controls the inflammatory response. A particular emphasis is given to the role of IL-10 and STAT3 in tumor-associated immunosuppression, where the functional inhibition of either molecule results in acquiescence to proinflammatory and anti-tumor Th1 type immune responses.


Dendritic Cell Th17 Cell Experimental Autoimmune Encephalomyelitis Unphosphorylated STAT3 Helper Cell Lineage 


  1. Aggarwal, B.B., et al., Signal transducer and activator of transcription-3, inflammation, and cancer: how intimate is the relationship? Ann N Y Acad Sci, 2009. 1171: p. 59–76.PubMedCrossRefGoogle Scholar
  2. Aksentijevich, I., et al., An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med, 2009. 360(23): p. 2426–37.PubMedCrossRefGoogle Scholar
  3. Anderson, C.F. and D.M. Mosser, A novel phenotype for an activated macrophage: the type 2 activated macrophage. J Leukoc Biol, 2002. 72(1): p. 101–6.PubMedGoogle Scholar
  4. Anderson, C.F., et al., CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med, 2007. 204(2): p. 285–97.PubMedCrossRefGoogle Scholar
  5. Aste-Amezaga, M., et al., Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. J Immunol, 1998. 160(12): p. 5936–44.PubMedGoogle Scholar
  6. Aziz, M.H., et al., Protein kinase Cepsilon interacts with Stat3 and regulates its activation that is essential for the development of skin cancer. Mol Carcinog, 2007. 46(8): p. 646–53.PubMedCrossRefGoogle Scholar
  7. Belkaid, Y., et al., The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of anti-IL-10 receptor antibody for sterile cure. J Exp Med, 2001. 194(10): p. 1497–506.PubMedCrossRefGoogle Scholar
  8. Bell, D., et al., In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med, 1999. 190(10): p. 1417–26.PubMedCrossRefGoogle Scholar
  9. Bennett, C.L., et al., The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet, 2001. 27(1): p. 20–1.PubMedCrossRefGoogle Scholar
  10. Berg, D.J., et al., Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J Clin Invest, 1995. 96(5): p. 2339–47.PubMedCrossRefGoogle Scholar
  11. Biswas, S.K., et al., A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood, 2006. 107(5): p. 2112–22.PubMedCrossRefGoogle Scholar
  12. Blackburn, S.D. and E.J. Wherry, IL-10, T cell exhaustion and viral persistence. Trends Microbiol, 2007. 15(4): p. 143–6.PubMedCrossRefGoogle Scholar
  13. Bollrath, J., et al., gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell, 2009. 15(2): p. 91–102.PubMedCrossRefGoogle Scholar
  14. Bromberg, J.F., et al., Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol, 1998. 18(5): p. 2553–8.PubMedGoogle Scholar
  15. Brooks, D.G., et al., Interleukin-10 determines viral clearance or persistence in vivo. Nat Med, 2006. 12(11): p. 1301–9.PubMedCrossRefGoogle Scholar
  16. Brooks, D.G., et al., IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J Exp Med, 2008. 205(3): p. 533–41.PubMedCrossRefGoogle Scholar
  17. Buettner, R., L.B. Mora, and R. Jove, Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res, 2002. 8(4): p. 945–54.PubMedGoogle Scholar
  18. Calzada-Wack, J.C., M. Frankenberger, and H.W. Ziegler-Heitbrock, Interleukin-10 drives human monocytes to CD16 positive macrophages. J Inflamm, 1996. 46(2): p. 78–85.PubMedGoogle Scholar
  19. Cassel, S.L. and P.B. Rothman, Chapter 3: Role of SOCS in allergic and innate immune responses. Adv Immunol, 2009. 103: p. 49–76.PubMedCrossRefGoogle Scholar
  20. Chaudhry, A., et al., CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science, 2009. 326(5955): p. 986–91.PubMedCrossRefGoogle Scholar
  21. Crawley, J.B., et al., Interleukin-10 stimulation of phosphatidylinositol 3-kinase and p70 S6 kinase is required for the proliferative but not the antiinflammatory effects of the cytokine. J Biol Chem, 1996. 271(27): p. 16357–62.PubMedCrossRefGoogle Scholar
  22. Croker, B.A., et al., SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol, 2003. 4(6): p. 540–5.PubMedCrossRefGoogle Scholar
  23. Denys, A., et al., 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, 2002. 168(10): p. 4837–45.PubMedGoogle Scholar
  24. Dercamp, C., et al., Distinct and overlapping roles of interleukin-10 and CD25+ regulatory T cells in the inhibition of antitumor CD8 T-cell responses. Cancer Res, 2005. 65(18): p. 8479–86.PubMedCrossRefGoogle Scholar
  25. Dikopoulos, N., et al., Type I IFN negatively regulates CD8+ T cell responses through IL-10-producing CD4+ T regulatory 1 cells. J Immunol, 2005. 174(1): p. 99–109.PubMedGoogle Scholar
  26. Driessler, F., et al., Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50. Clin Exp Immunol, 2004. 135(1): p. 64–73.PubMedCrossRefGoogle Scholar
  27. Ejrnaes, M., et al., Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med, 2006. 203(11): p. 2461–72.PubMedCrossRefGoogle Scholar
  28. El Kasmi, K.C., et al., General nature of the STAT3-activated anti-inflammatory response. J Immunol, 2006. 177(11): p. 7880–8.PubMedGoogle Scholar
  29. El Kasmi, K.C., et al., Cutting edge: a transcriptional repressor and corepressor induced by the STAT3-regulated anti-inflammatory signaling pathway. J Immunol, 2007. 179(11): p. 7215–9.PubMedGoogle Scholar
  30. Filippi, C.M. and M.G. von Herrath, IL-10 and the resolution of infections. J Pathol, 2008. 214(2): p. 224–30.PubMedCrossRefGoogle Scholar
  31. Finbloom, D.S. and K.D. Winestock, IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J Immunol, 1995. 155(3): p. 1079–90.PubMedGoogle Scholar
  32. Fiorentino, D.F., M.W. Bond, and T.R. Mosmann, Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med, 1989. 170(6): p. 2081–95.PubMedCrossRefGoogle Scholar
  33. Fitzgerald, D.C., et al., Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nat Immunol, 2007. 8(12): p. 1372–9.PubMedCrossRefGoogle Scholar
  34. Frobose, H., et al., Suppressor of cytokine Signaling-3 inhibits interleukin-1 signaling by targeting the TRAF-6/TAK1 complex. Mol Endocrinol, 2006. 20(7): p. 1587–96.PubMedCrossRefGoogle Scholar
  35. Fukao, T., et al., PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol, 2002. 3(9): p. 875–81.PubMedCrossRefGoogle Scholar
  36. Gaddi, P.J. and G.S. Yap, Cytokine regulation of immunopathology in toxoplasmosis. Immunol Cell Biol, 2007. 85(2): p. 155–9.PubMedCrossRefGoogle Scholar
  37. Gao, S.P. and J.F. Bromberg, Touched and moved by STAT3. Sci STKE, 2006. 2006(343): p. pe30.PubMedCrossRefGoogle Scholar
  38. 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-gamma and TNF-alpha. J Immunol, 1996. 157(2): p. 798–805.PubMedGoogle Scholar
  39. Gerosa, F., et al., Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-gamma and interleukin-10. J Exp Med, 1996. 183(6): p. 2559–69.PubMedCrossRefGoogle Scholar
  40. Gottfried, E., M. Kreutz, and A. Mackensen, Tumor-induced modulation of dendritic cell function. Cytokine Growth Factor Rev, 2008. 19(1): p. 65–77.PubMedCrossRefGoogle Scholar
  41. Grant, L.R., et al., Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells. Genes Immun, 2008. 9(4): p. 316–27.PubMedCrossRefGoogle Scholar
  42. Gray, M.J., et al., HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene, 2005. 24(19): p. 3110–20.PubMedCrossRefGoogle Scholar
  43. Grivennikov, S., et al., IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell, 2009. 15(2): p. 103–13.PubMedCrossRefGoogle Scholar
  44. Grutz, G., New insights into the molecular mechanism of interleukin-10-mediated immunosuppression. J Leukoc Biol, 2005. 77(1): p. 3–15.PubMedGoogle Scholar
  45. Guiducci, C., et al., Intralesional injection of adenovirus encoding CC chemokine ligand 16 inhibits mammary tumor growth and prevents metastatic-induced death after surgical removal of the treated primary tumor. J Immunol, 2004. 172(7): p. 4026–36.PubMedGoogle Scholar
  46. Guiducci, C., et al., Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res, 2005. 65(8): p. 3437–46.PubMedGoogle Scholar
  47. Guo, L., et al., IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci U S A, 2009. 106(32): p. 13463–8.PubMedCrossRefGoogle Scholar
  48. Hagemann, T., et al., “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med, 2008. 205(6): p. 1261–8.PubMedCrossRefGoogle Scholar
  49. Hagemann, T., et al., Regulation of macrophage function in tumors: the multifaceted role of NF-kappaB. Blood, 2009. 113(14): p. 3139–46.PubMedCrossRefGoogle Scholar
  50. Hammer, M., et al., Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10. Eur J Immunol, 2005. 35(10): p. 2991–3001.PubMedCrossRefGoogle Scholar
  51. Heimall, J., A. Freeman, and S.M. Holland, Pathogenesis of hyper IgE syndrome. Clin Rev Allergy Immunol, 2010. 38(1): p. 32–8.PubMedCrossRefGoogle Scholar
  52. Hinrichs, C.S., et al., Type 17 CD8+ T cells display enhanced antitumor immunity. Blood, 2009. 114(3): p. 596–9.PubMedCrossRefGoogle Scholar
  53. Hirotani, T., et al., The nuclear IkappaB protein IkappaBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria. J Immunol, 2005. 174(6): p. 3650–7.PubMedGoogle Scholar
  54. Hoentjen, F., et al., STAT3 regulates NF-kappaB recruitment to the IL-12p40 promoter in dendritic cells. Blood, 2005. 105(2): p. 689–96.PubMedCrossRefGoogle Scholar
  55. Hoffmann, K.F., A.W. Cheever, and T.A. Wynn, 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, 2000. 164(12): p. 6406–16.PubMedGoogle Scholar
  56. Holland, S.M., et al., STAT3 mutations in the hyper-IgE syndrome. N Engl J Med, 2007. 357(16): p. 1608–19.PubMedCrossRefGoogle Scholar
  57. Iliopoulos, D., H.A. Hirsch, and K. Struhl, An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell, 2009. 139(4): p. 693–706.PubMedCrossRefGoogle Scholar
  58. Jankovic, D. and G. Trinchieri, IL-10 or not IL-10: that is the question. Nat Immunol, 2007. 8(12): p. 1281–3.PubMedCrossRefGoogle Scholar
  59. 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, 2007. 204(2): p. 273–83.PubMedCrossRefGoogle Scholar
  60. Kidder, B.L., J. Yang, and S. Palmer, Stat3 and c-Myc genome-wide promoter occupancy in embryonic stem cells. PLoS One, 2008. 3(12): p. e3932.PubMedCrossRefGoogle Scholar
  61. Kitani, A., et al., Transforming growth factor (TGF)-beta1-producing regulatory T cells induce Smad-mediated interleukin 10 secretion that facilitates coordinated immunoregulatory activity and amelioration of TGF-beta1-mediated fibrosis. J Exp Med, 2003. 198(8): p. 1179–88.PubMedCrossRefGoogle Scholar
  62. Kontoyiannis, D., et al., Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. EMBO J, 2001. 20(14): p. 3760–70.PubMedCrossRefGoogle Scholar
  63. Koppelman, B., et al., Interleukin-10 down-regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity, 1997. 7(6): p. 861–71.PubMedCrossRefGoogle Scholar
  64. Kortylewski, M. and H. Yu, Stat3 as a potential target for cancer immunotherapy. J Immunother, 2007. 30(2): p. 131–9.PubMedCrossRefGoogle Scholar
  65. Kortylewski, M., et al., Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med, 2005. 11(12): p. 1314–21.PubMedCrossRefGoogle Scholar
  66. Kortylewski, M., et al., Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy. Cancer Res, 2009. 69(6): p. 2497–505.PubMedCrossRefGoogle Scholar
  67. Kortylewski, M., et al., In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses. Nat Biotechnol, 2009. 27(10): p. 925–32.PubMedCrossRefGoogle Scholar
  68. Kuhn, R., et al., Interleukin-10-deficient mice develop chronic enterocolitis. Cell, 1993. 75(2): p. 263–74.PubMedCrossRefGoogle Scholar
  69. Kuwata, H., et al., IL-10-inducible Bcl-3 negatively regulates LPS-induced TNF-alpha production in macrophages. Blood, 2003. 102(12): p. 4123–9.PubMedCrossRefGoogle Scholar
  70. Lang, R., et al., Shaping gene expression in activated and resting primary macrophages by IL-10. J Immunol, 2002. 169(5): p. 2253–63.PubMedGoogle Scholar
  71. Lang, R., et al., SOCS3 regulates the plasticity of gp130 signaling. Nat Immunol, 2003. 4(6): p. 546–50.PubMedCrossRefGoogle Scholar
  72. Levings, M.K., et al., IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol, 2001. 166(9): p. 5530–9.PubMedGoogle Scholar
  73. Liang, S.C., et al., Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med, 2006. 203(10): p. 2271–9.PubMedCrossRefGoogle Scholar
  74. Lighvani, A.A., et al., T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci U S A, 2001. 98(26): p. 15137–42.PubMedCrossRefGoogle Scholar
  75. Lu, H., et al., Treatment failure of a TLR-7 agonist occurs due to self-regulation of acute inflammation and can be overcome by IL-10 blockade. J Immunol, 2010. 184: p. 5360–7.PubMedCrossRefGoogle Scholar
  76. Lucas, M., et al., ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus. J Immunol, 2005. 175(1): p. 469–77.PubMedGoogle Scholar
  77. Ma, C.S., et al., Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med, 2008. 205(7): p. 1551–7.PubMedCrossRefGoogle Scholar
  78. Maeda, H., et al., TGF-beta enhances macrophage ability to produce IL-10 in normal and tumor-bearing mice. J Immunol, 1995. 155(10): p. 4926–32.PubMedGoogle Scholar
  79. Manetti, R., et al., Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones. J Exp Med, 1994. 179(4): p. 1273–83.PubMedCrossRefGoogle Scholar
  80. Maynard, C.L., et al., Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. Nat Immunol, 2007. 8(9): p. 931–41.PubMedCrossRefGoogle Scholar
  81. McGeachy, M.J., et al., TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol, 2007. 8(12): p. 1390–7.PubMedCrossRefGoogle Scholar
  82. Minegishi, Y., et al., Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature, 2007. 448(7157): p. 1058–62.PubMedCrossRefGoogle Scholar
  83. Moore, K.W., et al., Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol, 2001. 19: p. 683–765.PubMedCrossRefGoogle Scholar
  84. Mosser, D.M. and X. Zhang, Interleukin-10: new perspectives on an old cytokine. Immunol Rev, 2008. 226: p. 205–18.PubMedCrossRefGoogle Scholar
  85. Murray, P.J., The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci U S A, 2005. 102(24): p. 8686–91.PubMedCrossRefGoogle Scholar
  86. Murray, P.J., Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol, 2006. 6(4): p. 379–86.PubMedCrossRefGoogle Scholar
  87. Nelson, D.A., C.C. Petty, and K.L. Bost, Infection with murine gammaherpesvirus 68 exacerbates inflammatory bowel disease in IL-10-deficient mice. Inflamm Res, 2009. 58(12): p. 881–9.PubMedCrossRefGoogle Scholar
  88. Ng, D.C., et al., Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin. J Cell Biol, 2006. 172(2): p. 245–57.PubMedCrossRefGoogle Scholar
  89. Niu, G., et al., Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res, 1999. 59(20): p. 5059–63.PubMedGoogle Scholar
  90. Niu, G., et al., Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res, 2001. 61(8): p. 3276–80.PubMedGoogle Scholar
  91. Niu, G., et al., Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene, 2002. 21(13): p. 2000–8.PubMedCrossRefGoogle Scholar
  92. Nylen, S., et al., Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis. J Exp Med, 2007. 204(4): p. 805–17.PubMedCrossRefGoogle Scholar
  93. O’Garra, A., et al., Strategies for use of IL-10 or its antagonists in human disease. Immunol Rev, 2008. 223: p. 114–31.PubMedCrossRefGoogle Scholar
  94. O’Shea, J.J. and P.J. Murray, Cytokine signaling modules in inflammatory responses. Immunity, 2008. 28(4): p. 477–87.PubMedCrossRefGoogle Scholar
  95. O’Shea, J.J. and W.E. Paul, Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science, 2010. 327(5969): p. 1098–102.PubMedCrossRefGoogle Scholar
  96. Page, T.H., et al., Tyrosine kinases and inflammatory signalling. Curr Mol Med, 2009. 9(1): p. 69–85.PubMedCrossRefGoogle Scholar
  97. Peacock, J.W. and K.L. Bost, Murine gammaherpesvirus-68-induced interleukin-10 increases viral burden, but limits virus-induced splenomegaly and leukocytosis. Immunology, 2001. 104(1): p. 109–17.PubMedCrossRefGoogle Scholar
  98. Pearce, E.L., et al., Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science, 2003. 302(5647): p. 1041–3.PubMedCrossRefGoogle Scholar
  99. Penna, D., A. Schmidt, and F. Beermann, Tumors of the retinal pigment epithelium metastasize to inguinal lymph nodes and spleen in tyrosinase-related protein 1/SV40 T antigen transgenic mice. Oncogene, 1998. 17(20): p. 2601–7.PubMedCrossRefGoogle Scholar
  100. Perona-Wright, G., et al., Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe, 2009. 6(6): p. 503–12.PubMedCrossRefGoogle Scholar
  101. Perrot, I., et al., Dendritic cells infiltrating human non-small cell lung cancer are blocked at immature stage. J Immunol, 2007. 178(5): p. 2763–9.PubMedGoogle Scholar
  102. Pickert, G., et al., STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med, 2009. 206(7): p. 1465–72.PubMedCrossRefGoogle Scholar
  103. Rabinovich, G.A., D. Gabrilovich, and E.M. Sotomayor, Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol, 2007. 25: p. 267–96.PubMedCrossRefGoogle Scholar
  104. Rahimi, A.A., et al., STAT-1 mediates the stimulatory effect of IL-10 on CD14 expression in human monocytic cells. J Immunol, 2005. 174(12): p. 7823–32.PubMedGoogle Scholar
  105. Raz, R., et al., Essential role of STAT3 for embryonic stem cell pluripotency. Proc Natl Acad Sci U S A, 1999. 96(6): p. 2846–51.PubMedCrossRefGoogle Scholar
  106. Reddy, S., et al., An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med, 2009. 360(23): p. 2438–44.PubMedCrossRefGoogle Scholar
  107. Riley, J.K., et al., Interleukin-10 receptor signaling through the JAK-STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action. J Biol Chem, 1999. 274(23): p. 16513–21.PubMedCrossRefGoogle Scholar
  108. Robinson, D., et al., IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFkappaB. Immunity, 1997. 7(4): p. 571–81.PubMedCrossRefGoogle Scholar
  109. 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, 2004. 200(10): p. 1289–97.PubMedCrossRefGoogle Scholar
  110. Romagnani, S., Lymphokine production by human T cells in disease states. Annu Rev Immunol, 1994. 12: p. 227–57.PubMedCrossRefGoogle Scholar
  111. Roncarolo, M.G., et al., Type 1 T regulatory cells. Immunol Rev, 2001. 182: p. 68–79.PubMedCrossRefGoogle Scholar
  112. Rossato, M., et al., IL-10 modulates cytokine gene transcription by protein synthesis-independent and dependent mechanisms in lipopolysaccharide-treated neutrophils. Eur J Immunol, 2007. 37(11): p. 3176–89.PubMedCrossRefGoogle Scholar
  113. Rubtsov, Y.P., et al., Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity, 2008. 28(4): p. 546–58.PubMedCrossRefGoogle Scholar
  114. Sabat, R., et al., Biology of Interleukin-10, In Class II Cytokines, Zdanov, A., Editor. 2007, Kerala, India: Transworld Research Network. p. 107–26.Google Scholar
  115. Samavati, L., et al., STAT3 tyrosine phosphorylation is critical for interleukin 1 beta and interleukin-6 production in response to lipopolysaccharide and live bacteria. Mol Immunol, 2009. 46(8–9): p. 1867–77.PubMedCrossRefGoogle Scholar
  116. Sanjabi, S., et al., Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol, 2009. 9(4): p. 447–53.PubMedCrossRefGoogle Scholar
  117. Saraiva, M. and A. O’Garra, The regulation of IL-10 production by immune cells. Nat Rev Immunol, 2010. 10(3): p. 170–81.PubMedCrossRefGoogle Scholar
  118. 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. Immunity, 2009. 31(2): p. 209–19.PubMedCrossRefGoogle Scholar
  119. Schaljo, B., et al., Tristetraprolin is required for full anti-inflammatory response of murine macrophages to IL-10. J Immunol, 2009. 183(2): p. 1197–206.PubMedCrossRefGoogle Scholar
  120. Schindler, C., D.E. Levy, and T. Decker, JAK-STAT signaling: from interferons to cytokines. J Biol Chem, 2007. 282(28): p. 20059–63.PubMedCrossRefGoogle Scholar
  121. 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, 1998. 66(11): p. 5224–31.PubMedGoogle Scholar
  122. Sharif, M.N., et al., IFN-alpha priming results in a gain of proinflammatory function by IL-10: implications for systemic lupus erythematosus pathogenesis. J Immunol, 2004. 172(10): p. 6476–81.PubMedGoogle Scholar
  123. Sharma, A., et al., Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a. Proc Natl Acad Sci U S A, 2009. 106(14): p. 5761–6.PubMedCrossRefGoogle Scholar
  124. Shen, Y., et al., Essential role of STAT3 in postnatal survival and growth revealed by mice lacking STAT3 serine 727 phosphorylation. Mol Cell Biol, 2004. 24(1): p. 407–19.PubMedCrossRefGoogle Scholar
  125. Sica, A., et al., Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol, 2000. 164(2): p. 762–7.PubMedGoogle Scholar
  126. 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, 2006. 36(12): p. 3248–55.PubMedCrossRefGoogle Scholar
  127. Silva, R.A., T.F. Pais, and R. Appelberg, Blocking the receptor for IL-10 improves antimycobacterial chemotherapy and vaccination. J Immunol, 2001. 167(3): p. 1535–41.PubMedGoogle Scholar
  128. Spencer, J.V., The cytomegalovirus homolog of interleukin-10 requires phosphatidylinositol 3-kinase activity for inhibition of cytokine synthesis in monocytes. J Virol, 2007. 81(4): p. 2083–6.PubMedCrossRefGoogle Scholar
  129. Staples, K.J., et al., IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3. J Immunol, 2007. 178(8): p. 4779–85.PubMedGoogle Scholar
  130. Stearns, M.E., et al., Interleukin-10 induced activating transcription factor 3 transcriptional suppression of matrix metalloproteinase-2 gene expression in human prostate CPTX-1532 Cells. Mol Cancer Res, 2004. 2(7): p. 403–16.PubMedGoogle Scholar
  131. Stumhofer, J.S., et al., Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol, 2007. 8(12): p. 1363–71.PubMedCrossRefGoogle Scholar
  132. Sumi, T., et al., STAT3 is dispensable for maintenance of self-renewal in nonhuman primate embryonic stem cells. Stem Cells, 2004. 22(5): p. 861–72.PubMedCrossRefGoogle Scholar
  133. Sun, J., et al., Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med, 2009. 15(3): p. 277–84.PubMedCrossRefGoogle Scholar
  134. Takeda, K., et al., Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A, 1997. 94(8): p. 3801–4.PubMedCrossRefGoogle Scholar
  135. Takeda, K., et al., Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity, 1999. 10(1): p. 39–49.PubMedCrossRefGoogle Scholar
  136. Tamassia, N., et al., Uncovering an IL-10-dependent NF-{kappa}B recruitment to the IL-1ra promoter that is impaired in STAT3 functionally defective patients. FASEB J, 2010. 24: p. 1365–75.PubMedCrossRefGoogle Scholar
  137. Thompson, M.R., D. Xu, and B.R. Williams, ATF3 transcription factor and its emerging roles in immunity and cancer. J Mol Med, 2009. 87(11): p. 1053–60.PubMedCrossRefGoogle Scholar
  138. Trinchieri, G., Interleukin-10 production by effector T cells: Th1 cells show self control. J Exp Med, 2007. 204(2): p. 239–43.PubMedCrossRefGoogle Scholar
  139. Trumpfheller, C., et al., The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci U S A, 2008. 105(7): p. 2574–9.PubMedCrossRefGoogle Scholar
  140. Usui, T., et al., T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med, 2006. 203(3): p. 755–66.PubMedCrossRefGoogle Scholar
  141. Uze, G. and D. Monneron, IL-28 and IL-29: newcomers to the interferon family. Biochimie, 2007. 89(6–7): p. 729–34.PubMedGoogle Scholar
  142. Veldhoen, M., et al., Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol, 2008. 9(12): p. 1341–6.PubMedCrossRefGoogle Scholar
  143. Vicari, A.P. and G. Trinchieri, Interleukin-10 in viral diseases and cancer: exiting the labyrinth? Immunol Rev, 2004. 202: p. 223–36.PubMedCrossRefGoogle Scholar
  144. Vicari, A.P., et al., Reversal of tumor-induced dendritic cell paralysis by CpG immunosti­mulatory oligonucleotide and anti-interleukin 10 receptor antibody. J Exp Med, 2002. 196(4): p. 541–9.PubMedCrossRefGoogle Scholar
  145. Viswanathan, S.R. and G.Q. Daley, Lin28: A microRNA regulator with a macro role. Cell, 2010. 140(4): p. 445–9.PubMedCrossRefGoogle Scholar
  146. Wang, T., et al., Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med, 2004. 10(1): p. 48–54.PubMedCrossRefGoogle Scholar
  147. Weaver, C.T., et al., IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol, 2007. 25: p. 821–52.PubMedCrossRefGoogle Scholar
  148. Weaver, B.K., et al., ABIN-3: a molecular basis for species divergence in interleukin-10-induced anti-inflammatory actions. Mol Cell Biol, 2007. 27(13): p. 4603–16.PubMedCrossRefGoogle Scholar
  149. Weber-Nordt, R.M., et al., Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J Biol Chem, 1996. 271(44): p. 27954–61.PubMedCrossRefGoogle Scholar
  150. Wegrzyn, J., et al., Function of mitochondrial Stat3 in cellular respiration. Science, 2009. 323(5915): p. 793–7.PubMedCrossRefGoogle Scholar
  151. Weiner, H.L., Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev, 2001. 182: p. 207–14.PubMedCrossRefGoogle Scholar
  152. Wildin, R.S., et al., X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet, 2001. 27(1): p. 18–20.PubMedCrossRefGoogle Scholar
  153. Williams, L.M., et al., Interleukin-10 suppression of myeloid cell activation – a continuing puzzle. Immunology, 2004. 113(3): p. 281–92.PubMedCrossRefGoogle Scholar
  154. Williams, L.M., et al., Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages. J Biol Chem, 2007. 282(10): p. 6965–75.PubMedCrossRefGoogle Scholar
  155. Wohlfert, E. and Y. Belkaid, Plasticity of T reg at infected sites. Mucosal Immunol, 2010. 3(3): p. 213–5.PubMedCrossRefGoogle Scholar
  156. Wolk, K., et al., IL-22 increases the innate immunity of tissues. Immunity, 2004. 21(2): p. 241–54.PubMedCrossRefGoogle Scholar
  157. Wynn, T.A., IL-13 effector functions. Annu Rev Immunol, 2003. 21: p. 425–56.PubMedCrossRefGoogle Scholar
  158. Xu, Q., et al., Targeting Stat3 blocks both HIF-1 and VEGF expression induced by multiple oncogenic growth signaling pathways. Oncogene, 2005. 24(36): p. 5552–60.PubMedCrossRefGoogle Scholar
  159. Yamamoto, M. and K. Takeda, Role of nuclear IkappaB proteins in the regulation of host immune responses. J Infect Chemother, 2008. 14(4): p. 265–9.PubMedCrossRefGoogle Scholar
  160. Yang, J., et al., Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev, 2007. 21(11): p. 1396–408.PubMedCrossRefGoogle Scholar
  161. Yasukawa, H., et al., IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol, 2003. 4(6): p. 551–6.PubMedCrossRefGoogle Scholar
  162. Yen, H.R., et al., Tc17 CD8 T cells: functional plasticity and subset diversity. J Immunol, 2009. 183(11): p. 7161–8.PubMedCrossRefGoogle Scholar
  163. Yoshimura, A., T. Naka, and M. Kubo, SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol, 2007. 7(6): p. 454–65.PubMedCrossRefGoogle Scholar
  164. Yu, H. and R. Jove, The STATs of cancer – new molecular targets come of age. Nat Rev Cancer, 2004. 4(2): p. 97–105.PubMedCrossRefGoogle Scholar
  165. Yu, C.L., et al., Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science, 1995. 269(5220): p. 81–3.PubMedCrossRefGoogle Scholar
  166. Yu, H., D. Pardoll, and R. Jove, STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer, 2009. 9(11): p. 798–809.PubMedCrossRefGoogle Scholar
  167. Zeng, B., et al., Tumor-induced suppressor of cytokine signaling 3 inhibits toll-like receptor 3 signaling in dendritic cells via binding to tyrosine kinase 2. Cancer Res, 2008. 68(13): p. 5397–404.PubMedCrossRefGoogle Scholar
  168. Zhang, X., J.P. Edwards, and D.M. Mosser, Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription. J Immunol, 2006. 177(2): p. 1282–8.PubMedGoogle Scholar
  169. Zhang, S.Y., et al., Inborn errors of interferon (IFN)-mediated immunity in humans: insights into the respective roles of IFN-alpha/beta, IFN-gamma, and IFN-lambda in host defense. Immunol Rev, 2008. 226: p. 29–40.PubMedCrossRefGoogle Scholar
  170. Zhu, J., H. Yamane, and W.E. Paul, Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol, 2010. 28: p. 445–89.PubMedCrossRefGoogle Scholar
  171. Zou, W., Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer, 2005. 5(4): p. 263–74.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLc 2011

Authors and Affiliations

  1. 1.Cancer and Inflammation Program, Center for Cancer ResearchNational Cancer InstituteFrederickUSA

Personalised recommendations