Published online before print January 2, 2007

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(Journal of Leukocyte Biology. 2007;81:1044-1053.)
© 2007 by Society for Leukocyte Biology

Protective role of IFN- in collagen-induced arthritis conferred by inhibition of mycobacteria-induced granulocyte chemotactic protein-2 production

Hilde Kelchtermans^*,1, Sofie Struyf, Bert De Klerck^*, Tania Mitera^*, Marijke Alen^*, Lies Geboes^*, Maarten Van Balen^*, Chris Dillen^*, Willy Put, Conny Gysemans, Alfons Billiau^*, Jo Van Damme and Patrick Matthys^*

^* Laboratories of Immunobiology and
Molecular Immunology, Rega Institute for Medical Research, and
Laboratory of Experimental Medicine and Endocrinology, Campus Gasthuisberg O and N, University of Leuven, Leuven, Belgium

¹ Correspondence: Laboratory of Immunobiology, Rega Institute, University of Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium. E-mail: hilde.kelchtermans{at}rega.kuleuven.be

Mice with a disrupted IFN- system are remarkably susceptible to experimental autoimmune diseases, such as collagen-induced arthritis (CIA), which rely on the use of CFA. The inflammatory lesions of these IFN- knockout (KO) mice are characterized by an excessive proportion of neutrophils. Here, we show that the increased severity of CIA in IFN-R KO as compared with wild-type mice is accompanied by increased levels of the CXC chemokine granulocyte chemotactic protein-2 (GCP-2), a major neutrophil-attracting chemokine in mice. We demonstrated that the heat-killed mycobacteria present in CFA elicited production of GCP-2 in mouse embryo fibroblast cultures and that this production was inhibited by IFN-. Inhibition of GCP-2 production by IFN- was STAT-1-dependent. IFN- receptor KO mice treated with neutralizing anti-GCP-2 antibodies were protected from CIA, indicating the in vivo importance of GCP-2 in the pathogenesis of CIA. Our data support the notion that one of the mechanisms whereby endogenous IFN- mitigates the manifestations of CIA consists of inhibiting production of GCP-2, thereby limiting mobilization and infiltration of neutrophils, which are important actors in joint inflammation. These results may also be applicable to other experimental models of autoimmunity that rely on the use of CFA.

Key Words: mice • neutrophils • chemokines

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