Combined effects of IL-12 and IL-18 on the induction of collagen-induced arthritis.
IL-18 expression has recently been detected in rheumatoid arthritis (RA) synovial membrane. We investigated the mechanisms by which IL-18-induced collagen-induced arthritis in DBA/1 mice primed intradermally with type II bovine collagen in IFA and boosted i.p. 21 days later with CII in saline. Mice were injected i.p. with rIL-12, rIL-18, or both (100 ng) during days -1 to 4 and again on days 20-24. Control mice received PBS. Mice treated with IL-12 or IL-18 alone developed significantly higher incidence and more severe disease compared with controls. These were elevated further by combination treatment with IL-12 and IL-18. The cytokine treatments led to markedly enhanced synovial hyperplasia, cellular infiltration, and cartilage erosion compared with controls. Cytokine-treated mice produced significantly more IFN-gamma, TNF-alpha, and IL-6 than the controls. Interestingly, IL-18-treated mice produced more TNF-alpha and IL-6, but less IFN-gamma, compared with mice treated with IL-12. Furthermore, splenic macrophages from DBA/1 mice cultured in vitro with IL-18, but not IL-12, produced substantial amounts of TNF-alpha. Mice treated with IL-18 or IL-18 plus IL-12 produced markedly more IgG1 and IgG2a anti-collagen Ab compared with controls, whereas IL-12 treatment only led to an enhanced IgG2a response. Together these results demonstrate that IL-18 can promote collagen-induced inflammatory arthritis through mechanisms that may be distinct from those induced by IL-12.
Leung
B P
BP
Department of Immunology and Centre for Rheumatic Diseases, University of Glasgow, United Kingdom.
McInnes
I B
IB
Esfandiari
E
E
Wei
X Q
XQ
Liew
F Y
FY
D000818:Animals; D000941:Antigens / Q000276:immunology; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004338:Drug Combinations; D004357:Drug Synergism; D007074:Immunoglobulin G / Q000096:biosynthesis; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000008:administration & dosage*; D020382:Interleukin-18 / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D000941:Antigens; D016207:Cytokines; D004338:Drug Combinations; D007074:Immunoglobulin G; D020382:Interleukin-18; D018664:Interleukin-12; D003094:Collagen