Abstracts (complete list) - Wissenschaft Online

Ingo Irmler, Mieczyslaw Gajda, Rolf Bräuer
Exacerbation of Antigen induced Arthritis in IFN-γ-deficient
Mice as a Result of Unrestricted IL-17 Response
In rheumatoid arthritis (RA), Th cells are supposed to be involved in induction and
perpetuation of autoimmune disease with a dominance of the pro-inflammatory Th1
response. However, the role of IFN-γ, the major cytokine produced by Th1 cells, is still
incompletely defined. We investigated antigen-induced arthritis, an animal model of RA,
in IFN-γ-deficient and wild-type C57Bl/6.
Inflammatory response in the acute stage was strikingly increased in IFN-γ-deficient
mice, demonstrated by exacerbated joint swelling, DTH reaction and histopathological
assessment of arthritis. Intraarticular administration of exogenous IFN-γ significantly
suppressed inflammation in IFN-γ-deficient as well as in wild-type mice.
Increased production of IL-2, IL-4, IL-5, IL-6 and in particular IL-17 upon stimulation of
lymph node and spleen cells from IFN-γ-deficient mice was associated with a decreased
humoral immune response with low serum levels of total and antigen specific
immunoglobulins (IgG, IgG1, IgG2a, IgG2b, IgG3). The lack of endogenous IFN-γ
resulted in large numbers of neutrophil granulocytes infiltrating acute inflamed knee
joints. Monoclonal antibodies neutralising IL-17 diminished acute inflammation. In vitro,
we found that Th cell expansion and production of IL-17 upon re-stimulation was
effectively inhibited by IFN-γ in a dose-dependent manner. These results clearly
demonstrate in vivo a dominance of anti-inflammatory properties of IFN-γ during the
initial phase of AIA and suggest disease promoting effects of IFN-γ-deficiency acting via
IL-17 modulated pathways.