Regulation of pathogenic IL-17 responses in collagen-induced arthritis: roles of endogenous interferon-gamma and IL-4
AffiliationSection of Rheumatology, Department of Medicine, University of Arizona, 1501 N. Campbell Avenue, Rm 6310, Tucson, Arizona 85724, USA
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
Department of Pathology, University of Michigan, 1301 Catherine, 5240 Medical Science 1, Ann Arbor, Michigan 48109, USA
MetadataShow full item record
CitationArthritis Research & Therapy 2009, 11:R158 (doi:10.1186/ar2838)
JournalArthritis Research & Therapy
Rights© 2009 Sarkar et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection InformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at email@example.com.
AbstractINTRODUCTION:Interleukin (IL)-17 plays an important role in the pathogenesis of rheumatoid arthritis and the mouse model collagen-induced arthritis (CIA). Interferon(IFN)-gamma 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-gamma and IL-4.METHODS: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-gamma and/or IL-4. Systemic IL-17, IFN-gamma, 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.RESULTS:Joint inflammation was associated with a higher ratio of systemic IL-17/IFN-gamma. Neutralization of IFN-gamma accelerated the course of CIA and was associated with increased IL-17 levels in the serum and joints. The IFN-gamma/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-gamma and was associated with increased bone and cartilage damage without an increase in the levels of IL-17.CONCLUSIONS:IL-4 and IFN-gamma 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.
VersionFinal published version