title: Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammation.
abstract: Compared with its pro-inflammatory function, the mechanisms underlying the anti-inflammatory effect of IL-6 are poorly understood. IL-6 can cooperate with TGF-β to induce IL-10 production in Th17 cells in vitro. However, the effect of IL-6 on generation of Tr1 cells and the in vivo importance of this effect are mostly uncharacterized. In this study, we showed that in vitro, IL-6 can induce the generation of IL-10-producing Tr1 cells from naïve CD4 T cells, independently of IL-27 and TGF-β. IL-6 induces IL-21 production in CD4 T cells and IL-10-inducing effect of IL-6 requires both IL-21 and IL-2. Although IL-6 cannot induce IL-10 production in CD8 T cells in a cell-autonomous manner, it can do so indirectly through promoting CD4 T cell IL-21 production. The IL-10-producing T cells induced by IL-6 have phenotypic, genetic and functional traits of Tr1 cells and can suppress LPS-induced in vivo inflammatory response in an IL-10-dependent fashion. Blockade of IL-6 in two autoimmune inflammation models, induced respectively by anti-CD3 antibody or Treg-depletion, led to reduction in IL-10-producing T cells and exacerbated inflammation of lung and intestine. Thus, we delineated critical pathways involved in IL-6-induced generation of Tr1 cells and demonstrated the importance of this event in restraining autoimmune tissue inflammation.
authors.affiliation: Department of Immunology, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.
authors.forename: Jun-O
authors.initials: JO
authors.lastname: Jin
authors.forename: Xiaozhe
authors.initials: X
authors.lastname: Han
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D015551:Autoimmunity; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D018398:Homeodomain Proteins / Q000235:genetics; D007249:Inflammation; D018836:Inflammation Mediators; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D020381:Interleukin-17; D007376:Interleukin-2 / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D007422:Intestines / Q000276:immunology; D008070:Lipopolysaccharides; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D017252:CD3 Complex; D018398:Homeodomain Proteins; D018836:Inflammation Mediators; D020381:Interleukin-17; D007376:Interleukin-2; D015850:Interleukin-6; D007378:Interleukins; D008070:Lipopolysaccharides; C064658:RAG-1 protein; D016753:Interleukin-10; D000098546:Interleukin-21