Dual role of IL-12 in early and late stages of murine collagen type II arthritis.
IL-12 can promote Th1 responses, and early administration of IL-12 during immunization was shown to enhance expression of autoimmune collagen-induced arthritis (CIA). We now studied the impact of IL-12 at the stage of disease expression and during established CIA in DBA-1 mice. Accelerated onset and enhanced severity were provoked when i.p. injections of 100 ng of murine IL-12 (mIL-12) were given around the time of arthritis onset. Moreover, the onset of CIA could be ameliorated with anti-mIL-12 Abs, indicating that IL-12 is a pivotal mediator in the expression of CIA. In addition, the effect of anti-mIL-12 treatment was analyzed in established CIA. Continued treatment did not suppress established arthritis. Instead, these mice showed an impressive exacerbation of arthritis shortly after cessation of anti-mIL-12 treatment, indicative of impairment of endogenous control. Exaggerated disease was characterized by massive granulocyte influx and enhanced expression of IL-1 beta and TNF-alpha mRNA in the synovial tissue. Subsequently, we treated established collagen arthritis with recombinant mIL-12 for 7 days. Profound suppression of the arthritis score was noted, including reduced influx of cells and diminished cartilage damage. Tenfold enhanced levels of IL-10 were detected in sera of mIL-12-treated mice, and up-regulated mRNA levels of IL-10, IFN-gamma, and IL-12 were measured in synovial tissue. Finally, the anti-inflammatory effect of IL-12 on CIA could be reversed by coadministration of anti-IL-10 Abs. This study indicates that IL-12 has a stimulatory role in early arthritis expression, whereas it has a suppressive role in the established phase of collagen arthritis.
Joosten
L A
LA
Department of Rheumatology, University Hospital, Nijmegen, The Netherlands.
Lubberts
E
E
Helsen
M M
MM
van den Berg
W B
WB
D000818:Animals; D000906:Antibodies / Q000097:blood; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002417:Cattle; D003094:Collagen / Q000276:immunology*; D005260:Female; D016753:Interleukin-10 / Q000502:physiology; D018664:Interleukin-12 / Q000502:physiology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000627:therapeutic use; D013997:Time Factors
D000906:Antibodies; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D003094:Collagen