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Regulation of pathogenic IL-17 responses in collagen-induced arthritis: roles of endogenous interferon-gamma and IL-4

Sujata Sarkar1*, Laura A Cooney2, Peter White2, Deborah B Dunlop1, Judith Endres2, Julie M Jorns3, Matthew J Wasco3 and David A Fox2

Author Affiliations

1 Section of Rheumatology, Department of Medicine, University of Arizona, 1501 N. Campbell Avenue, Rm 6310, Tucson, Arizona 85724, USA

2 Division of Rheumatology, Department of Internal Medicine, and Rheumatic Disease Core Center, University of Michigan, 1500 E Medical Center Drive, 3918 Taubman Center, SPC 5358, Ann Arbor, Michigan 48109, USA

3 Department of Pathology, University of Michigan, 1301 Catherine, 5240 Medical Science 1, Ann Arbor, Michigan 48109, USA

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Arthritis Research & Therapy 2009, 11:R158  doi:10.1186/ar2838

Published: 26 October 2009



Interleukin (IL)-17 plays an important role in the pathogenesis of rheumatoid arthritis and the mouse model collagen-induced arthritis (CIA). Interferon(IFN)-γ and IL-4 have been shown to suppress Th17 development in vitro, but their potential immunoregulatory roles in vivo are uncertain. The goals of this study were to determine the relationship between Th17 responses and disease severity in CIA and to assess regulation of IL-17 by endogenous IFN-γ and IL-4.


DBA1/LacJ mice were immunized with type II collagen in complete Freund's adjuvant (CFA) to induce arthritis, and treated with neutralizing antibody to IFN-γ and/or IL-4. Systemic IL-17, IFN-γ, and IL-4 were measured in serum. At the peak of disease, cytokine production was measured by ELISA of supernatants from spleen, lymph node and paw cultures. Paws were also scored for histologic severity of arthritis.


Joint inflammation was associated with a higher ratio of systemic IL-17/IFN-γ. Neutralization of IFN-γ accelerated the course of CIA and was associated with increased IL-17 levels in the serum and joints. The IFN-γ/IL-4/IL-17 responses in the lymphoid organ were distinct from such responses in the joints. Neutralization of IL-4 led to increased arthritis only in the absence of IFN-γ and was associated with increased bone and cartilage damage without an increase in the levels of IL-17.


IL-4 and IFN-γ both play protective roles in CIA, but through different mechanisms. Our data suggests that the absolute level of IL-17 is not the only determinant of joint inflammation. Instead, the balance of Th1, Th2 and Th17 cytokines control the immune events leading to joint inflammation.