Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18.
We have recently reported the presence and a potential proinflammatory role of IL-18 in the synovium of patients with rheumatoid arthritis. To obtain direct evidence that IL-18 plays an influential role in articular inflammation, we investigated the development of collagen-induced arthritis in a strain of mice lacking IL-18 (IL-18(-/-)) of DBA/1 background. IL-18(-/-) mice developed markedly reduced incidence of arthritis compared with heterozygous or wild-type mice. Of the IL-18(-/-) mice that developed arthritis, the severity of the disease was significantly reduced compared with the intact mice. This was accompanied by reduced articular inflammation and destruction evident on histology. IL-18(-/-) mice also had significantly reduced Ag-specific proliferation and proinflammatory cytokine (IFN-gamma, TNF-alpha, IL-6, and IL-12) production by spleen and lymph node cells in response to bovine type II collagen (CII) in vitro compared with wild-type mice, paralleled in vivo by a significant reduction in serum anti-CII IgG2a Ab level. Treatment with rIL-18 completely reversed the disease of the IL-18(-/-) mice to that of the wild-type mice. These data directly demonstrate a pivotal role of IL-18 in the development of inflammatory arthritis and suggest that antagonists to IL-18 may have therapeutic potential in rheumatic diseases.
Wei
X Q
XQ
Department of Immunology and Bacteriology, University of Glasgow, Glasgow, G11 6NT, United Kingdom.
Leung
B P
BP
Arthur
H M
HM
McInnes
I B
IB
Liew
F Y
FY
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis; D002478:Cells, Cultured; D003094:Collagen / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007274:Injections, Intraperitoneal; D020382:Interleukin-18 / Q000008:administration & dosage / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000008:administration & dosage; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D020382:Interleukin-18; D011994:Recombinant Proteins; D003094:Collagen