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-Deficient Mice As a Result of Unrestricted IL-17 Response1Institute of Pathology, University Hospital, Jena, Germany
Proinflammatory Th1 responses are believed to be involved in the induction and perpetuation of rheumatoid arthritis. However, the role of IFN-
, the major cytokine produced by Th1 cells, is still incompletely defined. In the present study, we investigated the effects of IFN- deficiency (IFN-–/–) on the course of experimental murine Ag-induced arthritis (AIA). In the acute stage of disease, IFN-–/– AIA mice showed significantly increased inflammatory responses compared with wild-type C57BL/6 AIA mice, i.e., exacerbated joint swelling, increased delayed-type hypersensitivity reaction, and increased histopathological scores of arthritis. Intraarticular administration of exogenous IFN- at induction of AIA significantly suppressed these acute aggravation effects. Stimulated cells isolated from lymph nodes and spleen of IFN-–/– AIA mice showed increased production of IL-2, IL-4, IL-5, IL-6, but most prominently of IL-17. These elevations were paralleled by decreased humoral immune responses, with low serum levels of total and Ag-specific IgG (IgG1, IgG2ab, IgG2b, IgG3). At immunohistology, the knee joints of IFN-–/– AIA mice showed massive neutrophil granulocyte infiltration. Treatment with mAbs neutralizing IL-17 diminished the acute inflammation. In vitro, Th cell expansion and production of IL-17 upon restimulation were effectively and dose dependently inhibited by IFN-. These results clearly demonstrate that IFN- has anti-inflammatory properties during the initial phase of AIA, and indicate that IFN- deficiency exerts disease-promoting effects, preferentially via IL-17-modulated pathways.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Deutsche Forschungsgemeinschaft (BR 1372/9-1) and the Interdisciplinary Center for Clinical Research, Jena, Germany.
2 Address correspondence and reprint requests to Dr. Rolf Bräuer, Institut für Pathologie, Universitätsklinikum Jena, Ziegelmühlenweg 1, D-07740 Jena, Germany. E-mail address: Rolf.Braeuer{at}med.uni-jena.de
3 Abbreviations used in this paper: RA, rheumatoid arthritis; AIA, Ag-induced arthritis; CIA, collagen-induced arthritis; DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; mBSA, methylated BSA.
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