The factors that initiate and regulate the increased eicosanoid production and inflammatory infiltration of ulcerative colitis are not established. Our long-term aims are to determine the role of inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) in this inflammatory process, which may lead to new therapeutic strategies. Recombinant human and rabbit cytokines, specific bioassays and non-cross- reacting radioimmunoassays, DNA and RNA probes, immunohistochemistry and in situ hybridization techniques will be applied to a well established rabbit model of colon inflammation.
Specific aims are: 1) to determine the effects of cytokines on prostaglandin, thromboxane and leukotriene production in isolated rabbit colon tissue and the interactions with bradykinin; 2) to identify colon cells responding to IL-1 and TNF and to determine the mechanism of induced eicosanoid production; 3) to determine the mechanism of the apparent paradoxical protective effect of low-dose IL- 1 on induced colon inflammation; 4) to determine the relationship of cytokine production with inflammation and eicosanoid synthesis in rabbit immune colitis; 5) to identify colon cells producing cytokines during the inflammatory process in the colon; and 6) to determine the critical role of cytokine in initiating inflammation in this model using monoclonal antibodies against IL-1 or the IL-1 receptor. Each study will involve extensive validation techniques, including comparison of the effects of different recombinant products (IL-1alpha, IL-1beta, TNF, synthetic IL-1 analogs) with dose response testing and multiple tissue preparations (perfused colons, minced colon tissue, isolated cells), and comparison of radioimmunoassay quantitation with bioassay, Northern blot analysis and immunohistochemistry. Our extensive preliminary results data suggest that IL-1 is produced just prior to the sequence of histological events characteristic of the colitis lesions, that IL-1 is a regulator of eicosanoid production, that pretreatment with a low-dose of IL-1 reduces inflammation through a mechanism that requires prostaglandin synthesis, and that anti-inflammatory drug therapy may involve cytokine inhibition.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First Independent Research Support & Transition (FIRST) Awards (R29)
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General Medicine A Subcommittee 2 (GMA)
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University of Southern California
Schools of Medicine
Los Angeles
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Grivennikov, Sergei I; Cominelli, Fabio (2016) Colitis-Associated and Sporadic Colon Cancers: Different Diseases, Different Mutations? Gastroenterology 150:808-10
De Salvo, Carlo; Wang, Xiao-Ming; Pastorelli, Luca et al. (2016) IL-33 Drives Eosinophil Infiltration and Pathogenic Type 2 Helper T-Cell Immune Responses Leading to Chronic Experimental Ileitis. Am J Pathol 186:885-98
Bamias, Giorgos; Cominelli, Fabio (2015) Role of type 2 immunity in intestinal inflammation. Curr Opin Gastroenterol 31:471-6
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Pagnini, Cristiano; Arseneau, Kristen O; Cominelli, Fabio (2015) Safety considerations when using anti-TNF? therapy to treat Crohn's disease. Expert Opin Drug Saf 14:31-44
Del Pinto, Rita; Pietropaoli, Davide; Chandar, Apoorva K et al. (2015) Association Between Inflammatory Bowel Disease and Vitamin D Deficiency: A Systematic Review and Meta-analysis. Inflamm Bowel Dis 21:2708-17
Bamias, Giorgos; Arseneau, Kristen O; Cominelli, Fabio (2014) Cytokines and mucosal immunity. Curr Opin Gastroenterol 30:547-52
Bamias, Giorgos; Dahman, Mohamed I; Arseneau, Kristen O et al. (2013) Intestinal-specific TNF? overexpression induces Crohn's-like ileitis in mice. PLoS One 8:e72594
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