Protective role of IFN-gamma in collagen-induced arthritis conferred by inhibition of mycobacteria-induced granulocyte chemotactic protein-2 production.
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.
Kelchtermans
Hilde
H
Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, Minderbroederstraat 10, B-3000 Leuven, Belgium. hilde.kelchtermans@rega.kuleuven.be
Struyf
Sofie
S
De Klerck
Bert
B
Mitera
Tania
T
Alen
Marijke
M
Geboes
Lies
L
Van Balen
Maarten
M
Dillen
Chris
C
Put
Willy
W
Gysemans
Conny
C
Billiau
Alfons
A
Van Damme
Jo
J
Matthys
Patrick
P
D000818:Animals; D000917:Antibody Formation; D001169:Arthritis, Experimental / Q000276:immunology* / Q000382:microbiology; D002478:Cells, Cultured; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000276:immunology / Q000378:metabolism*; D002633:Chemotaxis; D024043:Collagen Type II / Q000276:immunology*; D015536:Down-Regulation; D007111:Immunity, Cellular; D007114:Immunization; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009161:Mycobacterium / Q000276:immunology / Q000378:metabolism*; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism
D054427:Chemokine CXCL6; D019743:Chemokines, CXC; D024043:Collagen Type II; D007371:Interferon-gamma