A proinflammatory role of IL-18 in the development of spontaneous autoimmune disease.
Serum from patients with systemic lupus erythematosus (SLE) contained significantly higher concentrations of IL-18 than normal individuals. MRL/lpr mice, which develop spontaneous lupus-like autoimmune disease, also had higher serum levels of IL-18 than wild-type MRL/++ mice. Daily injections of IL-18 or IL-18 plus IL-12 resulted in accelerated proteinuria, glomerulonephritis, vasculitis, and raised levels of proinflammatory cytokines in MRL/lpr mice. IL-18-treated MRL/lpr mice also developed a "butterfly" facial rash resembling clinical SLE. In contrast, MRL/lpr mice treated with IL-18 plus IL-12 did not develop a facial rash. The facial lesion in the IL-18-treated mice showed epidermal thickening with intense chronic inflammation accompanied by increased apoptosis, Ig deposition, and early systemic Th2 response compared with control or IL-12 plus IL-18-treated mice. These data therefore show that IL-18 is an important mediator of lupus-like disease and may thus be a novel target for therapeutic intervention of spontaneous autoimmune diseases.
Esfandiari
E
E
Department of Immunology and Bacteriology, Centre of Rheumatic Disease, Glasgow, United Kingdom.
McInnes
I B
IB
Lindop
G
G
Huang
F P
FP
Field
M
M
Komai-Koma
M
M
Wei
X
X
Liew
F Y
FY
D000328:Adult; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001327:Autoimmune Diseases / Q000209:etiology* / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000209:etiology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008875:Middle Aged
D000974:Antibodies, Antinuclear; D016207:Cytokines; D020382:Interleukin-18; D018664:Interleukin-12