RECOMBINANT INTERLEUKIN-1 RECEPTOR ANTAGONIST BLOCKS THE PROINFLAMMATORY ACTIVITY OF ENDOGENEOUS INTERLEUKIN-1 IN RABBIT IMMUNE COLITIS

The effects of human recombinant interleukin-1 receptor antagonist (IL-1ra) on inflammation, tissue damage, and production of inflammatory mediators in rabbit formalin-immune complex colitis were examined. Treatment of rabbits with intravenous administration of IL-1ra before and periodically throughout the first 43 hours after the induction of colitis (total 7 doses) suppressed inflammation and tissue damage in a dose-related manner. Maximum inhibition of inflammatory index (from 3.0 ± 0.3 to 0.8 ± 0.3, P < 0.001), edema (from 2.3 ± 0.2 to 0.6 ± 0.2, P < 0.001), percent of mucosal necrosis (from 44% ± 7% to 7% ± 3%, P < 0.02) and myeloperoxidase (MPO) activity (from 4.9 ± 1.0 U/g to 1.0 ± 0.3 U/g, P < 0.001) occurred with the dose of 5 mg/kg. Colonic prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production, measured in rectal dialysates by specific radioimmunoassays, was also dose dependently suppressed (from 1124 ± 319 pg/mL to 190 ± 75 pg/mL, P < 0.001 and 568 ±192 pg/mL to 92 ± 51 pg/mL, P < 0.001, respectively, at 5 mg/kg). In contrast, colonic IL-1α tissue levels measured by a specific radioimmunoassay after tissue extraction were similar in all groups. When only two doses of IL-1ra, 10 minutes before and 3 hours after the induction of colitis were given, there was no longer an inhibitory effect on inflammation or production of inflammatory mediators. However, delaying the initial IL-1ra treatment 3 hours after the induction of colitis (total 6 doses) was effective in reducing inflammatory index (by 60%), MPO activity (by 79%), PGE2 (by 62%), and LTB4 (by 72%) whereas colonic IL-1α levels were unchanged compared with vehicle-treated animals. These studies show the ability of human recombinant IL-1 receptor antagonist to suppress the proinflammatory activity of IL-1 produced in the colon during the induction and progression of rabbit immune complex colitis. © 1992.