title: The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells.
abstract: IL-6 is a proinflammatory cytokine and its overproduction is implicated in a variety of inflammatory disorders. Recent in vitro analyses suggest that IL-6 is a key cytokine that determines the balance between Foxp3(+) regulatory T cells (Tregs) and Th17 cells. However, it remains unclear whether excessive IL-6 production in vivo alters the development and function of Foxp3(+) Tregs. In this study, we analyzed IL-6 transgenic (Tg) mice in which serum IL-6 levels are constitutively elevated. Interestingly, in IL-6 Tg mice, whereas peripheral lymphoid organs were enlarged, and T cells exhibited activated phenotype, Tregs were not reduced but rather increased compared with wild-type mice. In addition, Tregs from Tg mice normally suppressed proliferation of naive T cells in vitro. Furthermore, Tregs cotransferred with naive CD4 T cells into SCID-IL-6 Tg mice inhibited colitis as successfully as those transferred into control SCID mice. These results indicate that overproduction of IL-6 does not inhibit development or function of Foxp3(+) Tregs in vivo. However, when naive CD4 T cells alone were transferred, Foxp3(+) Tregs retrieved from SCID-IL-6 Tg mice were reduced compared with SCID mice. Moreover, the Helios(-) subpopulation of Foxp3(+) Tregs, recently defined as extrathymic Tregs, was significantly reduced in IL-6 Tg mice compared with wild-type mice. Collectively, these results suggest that IL-6 overproduced in vivo inhibits inducible Treg generation from naive T cells, but does not affect the development and function of natural Tregs.
authors.affiliation: Laboratory for Immune Signal, National Institute of Biomedical Innovation, Ibaraki City, Osaka 567-0085, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nakano
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Terabe
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kawahata
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Ohkawara
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Han
authors.forename: Barry
authors.initials: B
authors.lastname: Ripley
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Teppei
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kimura
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000637:transplantation
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508600:IL6 protein, human; D015850:Interleukin-6