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PMID: 19161426 Published · ppublish English Journal Article Review

Interleukin-10: new perspectives on an old cytokine.

Immunological reviews ·Vol. 226 ·2008-12-00 ·Pages 205-18

Mosser DM, Zhang X

Abstract

Interleukin-10 (IL-10) has long been recognized to have potent and broad-spectrum anti-inflammatory activity, which has been unequivocally established in various models of infection, inflammation, and even in cancer. However, because of the marginal successes of the initial clinical trials using recombinant IL-10, some of the interest in this cytokine as an anti-inflammatory therapeutic has diminished. New work showing IL-10 production from regulatory T cells and even T-helper 1 T cells has reinvigorated the field and revealed the power of this cytokine to influence immune responses. Furthermore, new preclinical studies suggest that combination therapies, using antibodies to IL-10 along with chemotherapy, can be effective in treating bacterial, viral, or neoplastic diseases. Studies to understand IL-10 gene expression in the various cell types may lead to new therapeutics to enhance or inhibit IL-10 production. In this review, we summarize what is known about the regulation of IL-10 gene expression by various immune cells. We speculate on the promise that this cytokine holds to influence immune responses and mitigate immune pathologies.

MeSH Terms
Animals Gene Expression Regulation Humans Inflammation/immunology,therapy Interleukin-10/genetics,immunology,therapeutic use Mice Polymorphism, Genetic/genetics Receptors, Interleukin-10/immunology,metabolism Transcription Factors/metabolism
Chemicals
Receptors, Interleukin-10 Transcription Factors Interleukin-10
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Mosser David M
Department of Cell Biology and Molecular Genetics, The Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA. dmosser@umd.edu
Zhang Xia
References (97)
97 references, click to expand
  1. Proinflammatory effects of IL-10 during human endotoxemia.
    J Immunol. 2000 Sep 1;165(5):2783-9 PMID: 10946310
  2. Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy.
    J Immunother. 2008 Sep;31(7):620-32 PMID: 18600182
  3. Functional analysis of -571 IL-10 promoter polymorphism reveals a repressor element controlled by sp1.
    J Immunol. 2004 Sep 1;173(5):3215-22 PMID: 15322183
  4. The JAK-STAT signaling pathway: input and output integration.
    J Immunol. 2007 Mar 1;178(5):2623-9 PMID: 17312100
  5. Interleukin-10 and the interleukin-10 receptor.
    Annu Rev Immunol. 2001;19:683-765 PMID: 11244051
  6. The protooncogene c-Maf is an essential transcription factor for IL-10 gene expression in macrophages.
    J Immunol. 2005 Mar 15;174(6):3484-92 PMID: 15749884
  7. Delivery of biologically active anti-inflammatory cytokines IL-10 and IL-1ra in vivo by the Shigella type III secretion apparatus.
    J Immunol. 2008 Mar 15;180(6):4292-8 PMID: 18322242
  8. Haplotype associated with low interleukin-10 production in patients with severe asthma.
    Lancet. 1998 Jul 11;352(9122):113 PMID: 9672280
  9. STAT-1-mediated repression of monocyte interleukin-10 gene expression in vivo.
    Eur J Immunol. 2006 Mar;36(3):623-30 PMID: 16482512
  10. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones.
    J Exp Med. 1989 Dec 1;170(6):2081-95 PMID: 2531194
  11. Reversal of tumor-induced dendritic cell paralysis by CpG immunostimulatory oligonucleotide and anti-interleukin 10 receptor antibody.
    J Exp Med. 2002 Aug 19;196(4):541-9 PMID: 12186845
  12. Protein kinase R-dependent regulation of interleukin-10 in response to double-stranded RNA.
    J Biol Chem. 2008 Sep 12;283(37):25132-25139 PMID: 18625702
  13. The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain.
    J Leukoc Biol. 2004 Aug;76(2):314-21 PMID: 15123776
  14. Resolution of a chronic viral infection after interleukin-10 receptor blockade.
    J Exp Med. 2006 Oct 30;203(11):2461-72 PMID: 17030951
  15. Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance.
    J Clin Invest. 2006 Apr;116(4):916-28 PMID: 16543948
  16. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B.
    Nat Immunol. 2007 Oct;8(10):1095-104 PMID: 17767162
  17. Role of Stat3 in lipopolysaccharide-induced IL-10 gene expression.
    J Immunol. 2000 Aug 1;165(3):1612-7 PMID: 10903771
  18. IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-gamma when combined with IL-18.
    Eur J Immunol. 1999 Sep;29(9):2658-65 PMID: 10508240
  19. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection.
    J Exp Med. 2008 Mar 17;205(3):533-41 PMID: 18332180
  20. Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding.
    J Biol Chem. 1999 Nov 5;274(45):31868-74 PMID: 10542212
  21. Dynamic and transient remodeling of the macrophage IL-10 promoter during transcription.
    J Immunol. 2006 Jul 15;177(2):1282-8 PMID: 16818788
  22. Interleukin-10 suppression of myeloid cell activation--a continuing puzzle.
    Immunology. 2004 Nov;113(3):281-92 PMID: 15500614
  23. IFN-alpha induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3.
    J Immunol. 2003 Jul 1;171(1):285-90 PMID: 12817009
  24. Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin.
    J Biol Chem. 2008 Apr 25;283(17):11689-99 PMID: 18256032
  25. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation.
    N Engl J Med. 2003 Dec 4;349(23):2201-10 PMID: 14657427
  26. ERK activation following macrophage FcgammaR ligation leads to chromatin modifications at the IL-10 locus.
    J Immunol. 2005 Jul 1;175(1):469-77 PMID: 15972681
  27. c-maf promotes T helper cell type 2 (Th2) and attenuates Th1 differentiation by both interleukin 4-dependent and -independent mechanisms.
    J Exp Med. 1998 Nov 16;188(10):1859-66 PMID: 9815263
  28. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins.
    Immunity. 2006 May;24(5):563-74 PMID: 16713974
  29. Silencing of endogenous IL-10 in human dendritic cells leads to the generation of an improved CTL response against human melanoma associated antigenic epitope, MART-1 27-35.
    Clin Immunol. 2008 Mar;126(3):251-9 PMID: 18249038
  30. Differential regulation of the stability of cytokine mRNAs in lipopolysaccharide-activated blood monocytes in response to interleukin-10.
    J Biol Chem. 1996 Aug 16;271(33):20108-12 PMID: 8702732
  31. Identification of a macrophage-specific chromatin signature in the IL-10 locus.
    J Immunol. 2005 Jul 15;175(2):1041-6 PMID: 16002704
  32. Anti-interleukin 10 receptor monoclonal antibody is an adjuvant for T helper cell type 1 responses to soluble antigen only in the presence of lipopolysaccharide.
    J Exp Med. 2000 Nov 20;192(10):1529-34 PMID: 11085755
  33. 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. 2006 Dec 1;177(11):7551-8 PMID: 17114424
  34. Selective regulation of cytokine induction by adenoviral gene transfer of IkappaBalpha into human macrophages: lipopolysaccharide-induced, but not zymosan-induced, proinflammatory cytokines are inhibited, but IL-10 is nuclear factor-kappaB independent.
    J Immunol. 1999 Mar 1;162(5):2939-45 PMID: 10072544
  35. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10.
    Science. 2000 Aug 25;289(5483):1352-5 PMID: 10958782
  36. Epstein-Barr virus-encoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling.
    Oncogene. 2008 Jul 10;27(30):4150-60 PMID: 18362887
  37. Role of STAT3 in glucocorticoid-induced expression of the human IL-10 gene.
    Mol Immunol. 2008 Jun;45(11):3230-7 PMID: 18403020
  38. Suppression of dendritic cell differentiation through cytokines released by Primary Effusion Lymphoma cells.
    Immunol Lett. 2008 Oct 30;120(1-2):37-41 PMID: 18680763
  39. Cytokine signaling modules in inflammatory responses.
    Immunity. 2008 Apr;28(4):477-87 PMID: 18400190
  40. IL-10 underlies distinct susceptibility of BALB/c and C57BL/6 mice to Mycobacterium avium infection and influences efficacy of antibiotic therapy.
    J Immunol. 2007 Jun 15;178(12):8028-35 PMID: 17548640
  41. 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 May 15;168(10):4837-45 PMID: 11994432
  42. Adenosine augments IL-10 production by macrophages through an A2B receptor-mediated posttranscriptional mechanism.
    J Immunol. 2005 Dec 15;175(12):8260-70 PMID: 16339566
  43. A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages.
    J Immunol. 2000 Feb 15;164(4):1940-51 PMID: 10657644
  44. 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 Jul 15;157(2):798-805 PMID: 8752931
  45. A role for mitogen-activated protein kinase and Ets-1 in the induction of interleukin-10 transcription by human immunodeficiency virus-1 Tat.
    Immunology. 2007 Jul;121(3):337-48 PMID: 17376198
  46. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29.
    J Allergy Clin Immunol. 2008 May;121(5):1108-11 PMID: 18405958
  47. BCL-3 and NF-kappaB p50 attenuate lipopolysaccharide-induced inflammatory responses in macrophages.
    J Biol Chem. 2004 Nov 26;279(48):49995-50003 PMID: 15465827
  48. Regulation of lipopolysaccharide sensitivity by IFN regulatory factor-2.
    J Immunol. 2003 Jun 1;170(11):5739-47 PMID: 12759457
  49. Not always the bad guys: B cells as regulators of autoimmune pathology.
    Nat Rev Immunol. 2008 May;8(5):391-7 PMID: 18437156
  50. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10.
    Nat Immunol. 2007 Dec;8(12):1363-71 PMID: 17994025
  51. Acute alcohol intake induces SOCS1 and SOCS3 and inhibits cytokine-induced STAT1 and STAT3 signaling in human monocytes.
    Alcohol Clin Exp Res. 2008 Sep;32(9):1565-73 PMID: 18616672
  52. IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases.
    Expert Opin Ther Targets. 2007 May;11(5):601-12 PMID: 17465720
  53. Circuitry of nuclear factor kappaB signaling.
    Immunol Rev. 2006 Apr;210:171-86 PMID: 16623771
  54. Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells.
    Genes Immun. 2008 Jun;9(4):316-27 PMID: 18401353
  55. Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1.
    Immunity. 2007 Dec;27(6):952-64 PMID: 18093541
  56. Regulation of IL-10 gene expression in Th2 cells by Jun proteins.
    J Immunol. 2005 Feb 15;174(4):2098-105 PMID: 15699140
  57. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis.
    J Exp Med. 2007 Feb 19;204(2):285-97 PMID: 17283207
  58. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines.
    Immunity. 1999 Jun;10(6):745-51 PMID: 10403649
  59. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival.
    Nat Med. 2004 Sep;10(9):942-9 PMID: 15322536
  60. Central nervous system expression of IL-10 inhibits autoimmune encephalomyelitis.
    J Immunol. 2001 Jan 1;166(1):602-8 PMID: 11123343
  61. Chromatin-level regulation of the IL10 gene in T cells.
    J Biol Chem. 2004 Nov 5;279(45):46818-25 PMID: 15319439
  62. Macrophage activation and polarization.
    Front Biosci. 2008 Jan 01;13:453-61 PMID: 17981560
  63. Oral IL-10 gene delivery in a microsphere-based formulation for local transfection and therapeutic efficacy in inflammatory bowel disease.
    Gene Ther. 2008 Sep;15(17):1200-9 PMID: 18418416
  64. Cutting edge: clustered AU-rich elements are the target of IL-10-mediated mRNA destabilization in mouse macrophages.
    J Immunol. 1999 Mar 1;162(5):2457-61 PMID: 10072482
  65. cAMP-induced Interleukin-10 promoter activation depends on CCAAT/enhancer-binding protein expression and monocytic differentiation.
    J Biol Chem. 2003 Feb 21;278(8):5597-604 PMID: 12493739
  66. Cutting edge: biasing immune responses by directing antigen to macrophage Fc gamma receptors.
    J Immunol. 2002 Apr 15;168(8):3697-701 PMID: 11937518
  67. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes.
    J Interferon Cytokine Res. 1999 Jun;19(6):563-73 PMID: 10433356
  68. Mast cell homeostasis: a fundamental aspect of allergic disease.
    Crit Rev Immunol. 2007;27(1):15-32 PMID: 17430094
  69. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group.
    Gastroenterology. 2000 Dec;119(6):1461-72 PMID: 11113067
  70. IL-10 induces IL-10 in primary human monocyte-derived macrophages via the transcription factor Stat3.
    J Immunol. 2007 Apr 15;178(8):4779-85 PMID: 17404258
  71. A common factor regulates both Th1- and Th2-specific cytokine gene expression.
    EMBO J. 1994 Feb 1;13(3):625-33 PMID: 8313907
  72. Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.
    J Exp Med. 2007 Feb 19;204(2):273-83 PMID: 17283209
  73. T(H)1 cells control themselves by producing interleukin-10.
    Nat Rev Immunol. 2007 Jun;7(6):425-8 PMID: 17525751
  74. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease.
    Clin Gastroenterol Hepatol. 2006 Jun;4(6):754-9 PMID: 16716759
  75. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse.
    Immunity. 2006 Dec;25(6):941-52 PMID: 17137799
  76. A2A adenosine receptors and C/EBPbeta are crucially required for IL-10 production by macrophages exposed to Escherichia coli.
    Blood. 2007 Oct 1;110(7):2685-95 PMID: 17525287
  77. Blocking the receptor for IL-10 improves antimycobacterial chemotherapy and vaccination.
    J Immunol. 2001 Aug 1;167(3):1535-41 PMID: 11466374
  78. Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in RAW 264.7 macrophages.
    J Leukoc Biol. 2008 May;83(5):1258-66 PMID: 18263767
  79. 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 Nov;96(5):2339-47 PMID: 7593621
  80. Functional cooperation of simian virus 40 promoter factor 1 and CCAAT/enhancer-binding protein beta and delta in lipopolysaccharide-induced gene activation of IL-10 in mouse macrophages.
    J Immunol. 2003 Jul 15;171(2):821-8 PMID: 12847250
  81. IL-10 is required to prevent immune hyperactivity during infection with Trypanosoma cruzi.
    J Immunol. 1997 Apr 1;158(7):3311-6 PMID: 9120288
  82. Interleukin 10 pretreatment protects target cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA class I expression.
    J Exp Med. 1994 Dec 1;180(6):2371-6 PMID: 7964510
  83. Cyclic adenosine monophosphate-responsive elements are involved in the transcriptional activation of the human IL-10 gene in monocytic cells.
    Eur J Immunol. 1999 Oct;29(10):3098-104 PMID: 10540320
  84. 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. 2001 Apr 27;276(17):13664-74 PMID: 11278848
  85. Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells.
    J Immunol. 1998 Apr 1;160(7):3188-93 PMID: 9531274
  86. CD4+ T-regulatory cells: toward therapy for human diseases.
    Immunol Rev. 2008 Jun;223:391-421 PMID: 18613849
  87. Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8(+) cytotoxic T lymphocytes.
    J Virol. 2000 May;74(10):4729-37 PMID: 10775611
  88. Post-transcriptional control of cytokine production.
    Nat Immunol. 2008 Apr;9(4):353-9 PMID: 18349815
  89. Mechanisms of interleukin-10-mediated immune suppression.
    Immunology. 2001 Jun;103(2):131-6 PMID: 11412299
  90. Distal enhancer elements transcribe intergenic RNA in the IL-10 family gene cluster.
    J Immunol. 2005 Dec 1;175(11):7437-46 PMID: 16301651
  91. Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses.
    J Exp Med. 2005 Feb 21;201(4):615-26 PMID: 15728239
  92. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI.
    Science. 1990 Jun 8;248(4960):1230-4 PMID: 2161559
  93. Interleukin-10-induced CD8 cell proliferation.
    Immunology. 1999 Sep;98(1):80-9 PMID: 10469237
  94. Pbx raises the DNA binding specificity but not the selectivity of antennapedia Hox proteins.
    Mol Cell Biol. 1997 Aug;17(8):4696-706 PMID: 9234726
  95. Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50.
    Clin Exp Immunol. 2004 Jan;135(1):64-73 PMID: 14678266
  96. Haplotype-independent costimulation of IL-10 secretion by SDF-1/CXCL12 proceeds via AP-1 binding to the human IL-10 promoter.
    J Immunol. 2007 Feb 1;178(3):1581-8 PMID: 17237407
  97. NF-kappaB1 (p50) homodimers differentially regulate pro- and anti-inflammatory cytokines in macrophages.
    J Biol Chem. 2006 Sep 8;281(36):26041-50 PMID: 16835236
Article Info
Journal
Immunological reviews
Abbr.
Immunol Rev
ISSN
1600-065X
DOI
10.1111/j.1600-065X.2008.00706.x
Email
dmosser@umd.edu
Published
2008-12-00
Pages
205-18
Language
English
Region
England
NLM ID
7702118
PMCID
PMC2724982
Subset
IM
Grants
NIAID NIH HHS · R01 AI049383 · United States
NIAID NIH HHS · R01 AI049383-07 · United States
External Links
PubMed source DOI: 10.1111/j.1600-065X.2008.00706.x PMC Full Text View journal details
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