title: Interferon-gamma regulates susceptibility to collagen-induced arthritis through suppression of interleukin-17.
abstract: OBJECTIVE
  The enhanced expression of experimental arthritis in the absence of interferon-gamma (IFNgamma) suggests that IFNgamma suppresses arthritis. Interleukin-17 (IL-17) is a pivotal T cell cytokine in arthritis, and in vitro studies have indicated that IFNgamma suppresses IL-17 production. We undertook this study to test the hypothesis that resistance to collagen-induced arthritis (CIA) in C57BL/6 (B6) mice is regulated by IFNgamma-mediated suppression of IL-17.
  
  
  METHODS
  Wild-type (WT) B6 mice, IFNgamma-knockout (KO) B6 mice, and DBA/1 mice were immunized with type II collagen (CII) in Freund's complete adjuvant (CFA). Lymphocytes from immunized mice were analyzed for cytokine production ex vivo by intracellular staining or restimulation with CII and enzyme-linked immunosorbent assays. In vivo blockade of IL-17 was achieved with an anti-IL-17 monoclonal antibody (mAb).
  
  
  RESULTS
  CII restimulation of T cells from CII/CFA-immunized mice resulted in an approximately 5-fold increase in IL-17 production in IFNgamma-KO B6 mice compared with WT B6 mice. Neutralization of IFNgamma increased IL-17 production in WT B6 mice, and neutralization of IL-4 had a synergistic effect. Interestingly, the prototypical CIA-susceptible strain DBA/1 also demonstrated a high IL-17 and a low IFNgamma cytokine profile compared with WT B6 mice. Administration of the anti-IL-17 mAb attenuated arthritis in DBA/1 mice and almost completely prevented expression of arthritis in IFNgamma-KO B6 mice.
  
  
  CONCLUSIONS
  These results indicate that sensitivity of IFNgamma-deficient B6 mice to CIA is associated with high IL-17 production and that this cytokine is required for expression of arthritis in this strain.
authors: Division of Rheumatology, University of Washington, Seattle, Washington 98195, USA.
authors: Cong-Qiu
authors: CQ
authors: Chu
authors: David
authors: D
authors: Swart
authors: Dina
authors: D
authors: Alcorn
authors: Joel
authors: J
authors: Tocker
authors: Keith B
authors: KB
authors: Elkon
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D024043:Collagen Type II / Q000276:immunology / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D041681:NIH 3T3 Cells / Q000187:drug effects / Q000378:metabolism; D013154:Spleen / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D004338:Drug Combinations; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate