title: IFN-gamma regulates the requirement for IL-17 in proteoglycan-induced arthritis.
abstract: The contribution of the proinflammatory cytokines IFN-gamma and IL-17 to the pathogenesis of experimental arthritis is controversial. In proteoglycan (PG)-induced arthritis (PGIA), severe arthritis is dependent on the production of IFN-gamma, whereas IL-17 is dispensable. In collagen-induced arthritis and Ag-induced arthritis, although high levels of IFN-gamma are secreted, disease is exacerbated in IFN-gamma or IFN-gamma receptor-deficient mice due to the ability of IFN-gamma to suppress IL-17 expression. In the current study, we investigated the effect of IFN-gamma on the IL-17 response and its consequences in PGIA. In PG-immunized IFN-gamma(-/-) mice, despite reduction in arthritis, the PG-specific CD4(+) T cell IL-17 response was significantly increased. Elevated IL-17 contributed to development of arthritis, as disease in IFN-gamma/IL-17(-/-) was significantly reduced in comparison with either IFN-gamma(-/-) or IL-17(-/-) mice. A contribution of IFN-gamma and IL-17 to the development of arthritis was also identified in T-bet(-/-) mice. PG-specific CD4(+) T cells from T-bet(-/-) mice produced reduced IFN-gamma and elevated concentrations of IL-17. Both IFN-gamma and IL-17 contribute to arthritis, as T-bet(-/-) mice lacking IL-17 (T-bet/IL-17(-/-)) were resistant, whereas wild-type, T-bet(-/-), and IL-17(-/-) mice were susceptible to PGIA. T cell proliferation and autoantibody production did not correlate with development of disease; however, expression of cytokines and chemokines in joint tissues demonstrate that IFN-gamma and IL-17 cooperatively contribute to inflammation. These results demonstrate that both IFN-gamma and IL-17 have the potential to induce PGIA, but it is the strength of the IFN-gamma response that regulates the contribution of each of these Th effector cytokines to disease.
authors.affiliation: Department of Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Doodes
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Cao
authors.forename: Keith M
authors.initials: KM
authors.lastname: Hamel
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wang
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Rodeghero
authors.forename: Katalin
authors.initials: K
authors.lastname: Mikecz
authors.forename: Tibor T
authors.initials: TT
authors.lastname: Glant
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Alison
authors.initials: A
authors.lastname: Finnegan
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011509:Proteoglycans / Q000008:administration & dosage / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism
chemical_list: D018836:Inflammation Mediators; D020381:Interleukin-17; D011509:Proteoglycans; D007371:Interferon-gamma