There is increasing evidence that the regulation of IL-1 and its natural receptor antagonist, namely the IL-1ra, represents a crucial step in the cascade of biochemical and cellular events contributing to the progression of persistence of inflammation. Administration of recombinant human IL-1ra reduces the severity of disease in animal models of lethal endotoxemia, sepsis, arthritis, colitis, graft-versus- host disease and insulin-dependent diabetes. In addition, preliminary studies have shown the efficacy of IL-1ra treatment in human septic shock and rheumatoid arthritis. This proposal will test the hypothesis that a dysregulation of intestinal IL-1 and IL-1ra may be a key mechanism of perpetuation of inflammation and tissue damage in inflammatory bowel disease (IBD). Recombinant human cytokines, specific non-cross-reacting radioimmunoassays (RIA), and DNA and RNA probes will be applied to tissue and cell preparations from patients with ulcerative colitis and Crohn's disease. Our extensive preliminary data suggest that the ratio of IL-1ra to IL-1 is significantly decreased in intestinal tissues and cells from IBD, that lamina propria mononuclear cells express both IL-1 and IL-1ra, and that intestinal epithelial cells produce large amounts of IL-1ra but not IL-1.
The specific aims are to: 1) Determine the intestinal balance of IL-1 and IL-1ra in IBD. We will compare IL-1alpha, IL-1beta and IL-1ra levels in whole tissue, and lamina propria mononuclear cells and epithelial cells from control and IBD patients; 2) Determine the regulation of IL-1 and IL-1ra synthesis in intestinal mucosal cells. We will study which factors are involved in regulation of IL-1 and IL-ra synthesis; 3) Determine the cellular source of intestinal IL-1 and IL-1ra. Determination of the sites of IL- 1 and IL-1ra expression is an important issue. We will localize IL-1 and IL-1ra in intestinal tissue from control and IBD patients; 4) Assess the effects of exogenous IL-1ra on synthesis of other proinflammatory cytokines, including Il-6, IL-8 and TNF. We will test the hypothesis that IL-1 is a primary mediator of intestinal inflammation regulating the expression of other proinflammatory cytokines. Each study will involve extensive validation techniques, including comparison of RIA quantitation with ELISA, Northern blot analysis, immunohistochemistry and in situ hybridization techniques.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045740-02
Application #
3247256
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1992-09-30
Project End
1995-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Redlitz, Karen H; Yamshchikov, Vladimir F; Cominelli, Fabio (2004) Differential contribution of IL-1Ra isoforms to allele-specific IL-1Ra mRNA accumulation. J Interferon Cytokine Res 24:253-60
Yamshchikov, Vladimir F; Mishina, Margarita; Cominelli, Fabio (2002) A possible role of IL-1ra 3'-untranslated region in modulation of protein production. Cytokine 17:98-107
Compton, R F; Sandborn, W J; Yang, H et al. (1997) A new syndrome of Crohn's disease and pachydermoperiostosis in a family. Gastroenterology 112:241-9
Cominelli, F; Pizarro, T T (1996) Interleukin-1 and interleukin-1 receptor antagonist in inflammatory bowel disease. Aliment Pharmacol Ther 10 Suppl 2:49-53;discussion 54
Laine, L; Sloane, R; Ferretti, M et al. (1995) A randomized double-blind comparison of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production. Gastrointest Endosc 42:428-33
Casini-Raggi, V; Kam, L; Chong, Y J et al. (1995) Mucosal imbalance of IL-1 and IL-1 receptor antagonist in inflammatory bowel disease. A novel mechanism of chronic intestinal inflammation. J Immunol 154:2434-40
Casini-Raggi, V; Monsacchi, L; Vosbeck, K et al. (1995) Anti-inflammatory effects of CGP 47969A, a novel inhibitor of proinflammatory cytokine synthesis, in rabbit immune colitis. Gastroenterology 109:812-8
Ferretti, M; Casini-Raggi, V; Pizarro, T T et al. (1994) Neutralization of endogenous IL-1 receptor antagonist exacerbates and prolongs inflammation in rabbit immune colitis. J Clin Invest 94:449-53
Cominelli, F; Bortolami, M; Pizarro, T T et al. (1994) Rabbit interleukin-1 receptor antagonist. Cloning, expression, functional characterization, and regulation during intestinal inflammation. J Biol Chem 269:6962-71