Exacerbation of antigen-induced arthritis in IFN-gamma-deficient mice as a result of unrestricted IL-17 response.
Proinflammatory Th1 responses are believed to be involved in the induction and perpetuation of rheumatoid arthritis. However, the role of IFN-gamma, the major cytokine produced by Th1 cells, is still incompletely defined. In the present study, we investigated the effects of IFN-gamma deficiency (IFN-gamma(-/-)) on the course of experimental murine Ag-induced arthritis (AIA). In the acute stage of disease, IFN-gamma(-/-) 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-gamma at induction of AIA significantly suppressed these acute aggravation effects. Stimulated cells isolated from lymph nodes and spleen of IFN-gamma(-/-) 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, IgG2a(b), IgG2b, IgG3). At immunohistology, the knee joints of IFN-gamma(-/-) 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-gamma. These results clearly demonstrate that IFN-gamma has anti-inflammatory properties during the initial phase of AIA, and indicate that IFN-gamma deficiency exerts disease-promoting effects, preferentially via IL-17-modulated pathways.
Irmler
Ingo M
IM
Institute of Pathology, University Hospital, Jena, Germany.
Gajda
Mieczyslaw
M
Bräuer
Rolf
R
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D000917:Antibody Formation / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002465:Cell Movement; D007167:Immunotherapy; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism
D000906:Antibodies; D000941:Antigens; D020381:Interleukin-17; D007371:Interferon-gamma