title: Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis.
abstract: PURPOSE. Both Th17 and Th1 cells contribute to experimental autoimmune uveoretinitis (EAU). Interleukin-6 (IL-6) blockade inhibits Th17 differentiation in EAU and potently suppresses ocular inflammation, although its effect on Th1 cells is unknown. To clarify the mechanism of IL-6 blockade, the authors investigated T helper cells with particular focus on Th1 and regulatory T cells (Treg) in EAU of IL-6 gene knockout (KO) mice. METHODS. EAU was induced in wild-type (WT) mice and in mice lacking IL-6 (IL-6KO), IL-17 (IL-17KO), and IFN-γ (GKO) on a C57BL/6 background. Clinical scores of EAU, cytokine levels in supernatants from ocular tissue homogenates, and T helper cell differentiation in lymph nodes in each mouse were examined. To study the roles of Treg cells, EAU was induced in IL-6KO mice treated with anti-CD25 monoclonal antibody (mAb) to deplete Treg cells in vivo. RESULTS. Inflammation was comparable between WT, IL-17KO, and GKO mice but was absent in IL-6KO mice. Th17 and interphotoreceptor retinoid binding protein (IRBP)-specific Th1 cells were increased in GKO and IL-17KO mice, respectively, whereas both populations were reduced in IL-6KO mice. Th1-dominant EAU in IL-17KO mice was suppressed by anti-IL-6R mAb treatment. Treg cell depletion in vivo induced EAU in IL-6KO mice. CONCLUSIONS. After the induction of EAU, IL-6 deficiency resulted in the inhibition of the IRBP-specific Th1 response and enhanced the generation of IRBP-specific Treg cells. Furthermore, Treg was needed to inhibit Th1 responses and ocular inflammation in IL-6KO mice. Protective effects of IL-6 signaling blockade in EAU involve not only Th17 cell inhibition but also IRBP-specific Treg cell promotion.
authors.affiliation: Department of Ophthalmology, Osaka University Graduate School of Medicine, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Haruta
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ohguro
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hohki
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Terabe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Kohji
authors.initials: K
authors.lastname: Nishida
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000276:immunology*; D015850:Interleukin-6 / Q000502:physiology*; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012173:Retinitis / Q000276:immunology / Q000517:prevention & control*; D012177:Retinol-Binding Proteins / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D014605:Uveitis / Q000276:immunology / Q000517:prevention & control*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D016207:Cytokines; D005136:Eye Proteins; D015850:Interleukin-6; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial