Leukotrienes induce cell-survival signaling in intestinal epithelial cells

Background & Aims: Inflammatory bowel conditions, particularly ulcerative c olitis, are associated with an increased incidence of neoplastic transforma tion. High levels of proinflammatory leukotrienes (LTs)and upregulated expr ession of cyclooxygenase (COX)-2 are characteristic of inflammation. Moreov er, COX-2 has been implicated in cell survival and early colon carcinogenes is, Other aspects of interest for intestinal cell viability are the levels of beta-catenin and the antiapoptotic protein Bcl-2. We investigated the po ssibility that LTs participate in the regulation of these survival factors. Methods: We used the human intestinal epithelial cell line Int 407 and the vat intestinal epithelial cell line IEC-6. immunoblotting was applied to a scertain protein expression and distribution, and enzyme immunoassay method ology was used to measure prostaglandin E-2 (PGE,) production. Apoptotic ab ility was assessed by trypan blue exclusion, Hoechst staining, DNA fragment ation, and a caspase-3 activity assay. Results: LTD4 and LTB4, but not LTC4 , caused a time- and dose-dependent increase in expression and/or membrane accumulation of COX-2, beta-catenin, and Bcl-2, as well as PGE(2) productio n, Apoptosis assays showed that the effects of LTs on these transformation- associated proteins correlated well with the ability of these LTs to reduce programmed cell death, Conclusions: The results suggest that inflammatory conditions are associated with the expression and distribution of proteins that are characteristic of transformed cells; such conditions may involve a signaling mechanism comprising an altered rate of apoptosis.