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 dur ing immunization was shown to enhance expression of autoimmune collage n-induced arthritis (CIA), We now studied the impact of IL-12 at the s tage of disease expression and during established CIA in DBA-1 mice. A ccelerated onset and enhanced severity were provoked when i.p, injecti ons of 100 ng of murine IL-12 (mIL-12) were given around the time of a rthritis onset. Moreover, the onset of CIA could be ameliorated with a nti-mIL-12 Abs, indicating that IL-12 is a pivotal mediator in the exp ression of CIA, In addition, the effect of anti-mIL-12 treatment was a nalyzed in established CIA, Continued treatment did not suppress estab lished arthritis, Instead, these mice showed an impressive exacerbatio n of arthritis shortly after cessation of anti-mIL-12 treatment, indic ative of impairment of endogenous control. Exaggerated disease was cha racterized by massive granulocyte influx and enhanced expression of IL -1 beta and TNF-alpha mRNA in the synovial tissue, Subsequently, we tr eated established collagen arthritis with recombinant mIL-12 for 7 day s. Profound suppression of the arthritis score was noted, including re duced influx of cells and diminished cartilage damage, Tenfold enhance d 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 CI A could be reversed by coadministration of anti-IL-10 Abs. This study indicates that IL-12 has a stimulatory role in early arthritis express ion, whereas it has a suppressive role in the established phase of col lagen arthritis.