Regulation of pathogenic IL-17 responses in collagen-induced arthritis: roles of endogenous interferon-gamma and IL-4. Arthritis Res Ther 2009;11(5):R158
Date
10/27/2009Pubmed ID
19852819Pubmed Central ID
PMC2787258DOI
10.1186/ar2838Scopus ID
2-s2.0-75649140602 (requires institutional sign-in at Scopus site) 79 CitationsAbstract
INTRODUCTION: 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.
Author List
Sarkar S, Cooney LA, White P, Dunlop DB, Endres J, Jorns JM, Wasco MJ, Fox DAAuthor
Julie M. Jorns MD Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Neutralizing
Arthritis, Experimental
Arthritis, Rheumatoid
Cell Separation
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Interferon-gamma
Interleukin-17
Interleukin-4
Male
Mice
Mice, Inbred DBA
T-Lymphocyte Subsets
