Interleukin 1 (IL-1) gene expression, synthesis, and effect of specific IL-1 receptor blockade in rabbit immune complex colitis

• Published in: The Journal of clinical investigation Vol. 86; no. 3; pp. 972 - 980
• Main Authors: COMINELLI, F, NAST, C. C, CLARK, B. D, SCHINDLER, R, LLERENA, R, EYSSELEIN, V. E, THOMPSON, R. C, DINARELLO, C. A
• Format: Journal Article
• Language: English
• Published: Ann Arbor, MI American Society for Clinical Investigation 01.09.1990
• Subjects: Antigen-Antibody Complex; Biological and medical sciences; Blotting, Northern; Colitis - pathology; Colitis - physiopathology; Edema; Gene Expression; Immunopathology; Interleukin-1 - genetics; Interleukin-1 - metabolism; Leukotriene B4 - biosynthesis; Medical sciences; Necrosis; Prostaglandins E - biosynthesis; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - physiology; Receptors, Interleukin-1; Time Factors; Immunopathology; Vertebrata; Mammalia; Interleukin 1; Rabbit; Colitis; Lagomorpha; Gene expression
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci114799

Interleukin 1 (IL-1) may be a key mediator of inflammation and tissue damage in inflammatory bowel disease (IBD). In rabbits with immune complex-induced colitis, IL-1 alpha and beta mRNA levels were detectable at 4 h, peaked at 12 but were absent at 96 h after the induction of colitis. Colonic IL-1 tissue levels were measured by specific radioimmunoassays. IL-1 alpha was significantly elevated at 4 h (9.4 +/- 1.5 ng/g colon), progressively increased at 48 h (31 +/- 5.8 ng/g) and then decreased by 96 h (11.5 +/- 3.4 ng/g). IL-1 beta levels were 2.0 +/- 0.5 ng/g colon at 4 h, 5.0 +/- 1.6 ng/g at 48 h and undetectable by 96 h. By comparison, colonic levels of PGE2 and LTB4 were unchanged during the first 12 h and did not become elevated until 24 h. IL-1 alpha levels were highly correlated with inflammation (r = 0.885, P less than 0.0001), edema (r = 0.789, P less than 0.0001) and necrosis (r = 0.752, P less than 0.0005). Treatment with a specific IL-1 receptor antagonist (IL-1 ra) before and during the first 33 h after the administration of immune complexes markedly reduced inflammatory cell infiltration index (from 3.2 +/- 0.4 to 1.4 +/- 0.3, P less than 0.02), edema (from 2.2 +/- 0.4 to 0.6 +/- 0.3, P less than 0.01) and necrosis (from 43 +/- 10% to 6.6 +/- 3.2%, P less than 0.03) compared to vehicle-matched colitis animals. These studies demonstrate that (a) IL-1 gene expression and synthesis occur early in the course of immune complex-induced colitis; (b) are significantly elevated for 12 h before the appearance of PGE2 and LTB4; (c) tissue levels of IL-1 correlate with the degree of tissue inflammation and; (d) specific blockade of IL-1 receptors reduces the inflammatory responses associated with experimental colitis.