Interleukin-1 in the pathogenesis of and protection from inflammatory bowel disease.
Inflammatory bowel disease affects millions of people, some with fatal consequences. Little is known about the factors which contribute to its pathogenesis particularly regarding cytokine production and action. In this paper we summarize our recent findings using the rabbit model for immune complex-generated experimental colitis, a model which is similar to ulcerative colitis in humans. Recombinant human IL-1 was perfused through rabbit colons and we observed elevated levels of PGE2, TxB2 and 6-keto-PGF1 alpha, the stable metabolite of PGI2. Using radioimmunoassays specific for rabbit IL-1 alpha and IL-1 beta, we induced immune complex colitis and measured the generation of these IL-1's in various tissues. Markedly elevated levels of IL-1 were detected only in inflamed tissues. The levels of IL-1 correlated with the degree of inflammation as judged by a blinded assessment of pathological changes. Similar to other disease models in which small doses of the agonist can afford protection or result in a state of "desensitization" when administered prior to the onset of the disease, we accordingly injected rabbits with a single, small (300 ng/kg) dose of IL-1 and observed a significant reduction in the inflammatory index and necrosis of immune complex colitis. However, unlike other models of IL-1-induced protection, in this model cyclooxygenase products were required since we prevented the IL-1-induced protection with a single dose of ibuprofen given at the same time as the IL-1. This correlated with the reduction in IL-1-induced PGE2. These results demonstrate that IL-1 plays a key role in the pathogenesis of inflammatory bowel disease in the rabbit and that the protection afforded by a low dose of IL-1 24 hours before the onset of the colitis requires IL-1-induced cyclooxygenase products.
Cominelli
F
F
Division of Gastroenterology, Harbor-UCLA Medical Center, Torrance.
Dinarello
C A
CA
D000818:Animals; D003092:Colitis / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000517:prevention & control*; D007375:Interleukin-1 / Q000502:physiology / Q000627:therapeutic use*; D011817:Rabbits
D007375:Interleukin-1