Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Hematology, Immunology, mice, neutrophils, chemokines, EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS, DELAYED-TYPE HYPERSENSITIVITY, MACROPHAGE INFLAMMATORY PROTEIN-2, RECOMBINANT INTERFERON-GAMMA, RECEPTOR-DEFICIENT MICE, INVIVO IMMUNE-RESPONSE, RED-BLOOD-CELLS, RHEUMATOID-ARTHRITIS, MONOCLONAL-ANTIBODY, AUTOIMMUNE ENCEPHALOMYELITIS, Animals, Antibody Formation, Arthritis, Experimental, Cells, Cultured, Chemokine CXCL6, Chemokines, CXC, Chemotaxis, Collagen Type II, Down-Regulation, Immunity, Cellular, Immunization, Interferon-gamma, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mycobacterium, Synovial Fluid, 0601 Biochemistry and Cell Biology, 1107 Immunology, 3204 Immunology

Abstract:

Mice with a disrupted IFN-gamma 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-gamma knockout (KO) mice are characterized by an excessive proportion of neutrophils. Here, we show that the increased severity of CIA in IFN-gammaR 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-gamma. Inhibition of GCP-2 production by IFN-gamma was STAT-1-dependent. IFN-gamma 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-gamma 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.