Involvement of Eicosanoid Signaling in Intestinal Epithelial Cell Survival

Sammanfattning: Eicosanoids are known to be involved in many different aspects of eukaryotic physiology and pathology. Notably, over the past 10 years much attention has been given to cyclooxygenase-2 (COX-2) due to its involvement in colorectal cancer. Less is known about the other major branch of arachidonic acid metabolism, namely the lipoxygenases (LO). The cysteinyl leukotrienes (CysLTs) are a family of metabolites derived from 5-LO, and they are fairly well known because they play a pathogenic role in asthmatic disease. One member of this family, LTD₄ , aggravates asthma by exerting a powerful mitogenic effect on bronchiolar smooth muscle. In light of this observation and the fact that tissue levels of leukotrienes are high in the precancerous inflammatory bowel disease known as ulcerative colitis, the present studies focused mainly on the influence of leukotrienes in general, and LTD₄ in particular, on the survival of intestinal epithelial cells. Stimulation of intestinal epithelial cells with leukotrienes heightened the expression of colorectal oncogenic factors, such as COX-2, b-catenin, and Bcl-2, and simultaneously boosted the resistance of the cells to death induced by non-steroidal anti-inflammatory drugs. In analogy with this, levels of the LTD₄ receptor CysLT₁ R were significantly increased in roughly 50% of 84 colorectal cancer specimens, and this was accompanied by a markedly poorer disease outcome. Interestingly, in addition to the plasma membrane, the CysLT₁ R receptor was specifically found in cell nuclei, possibly because this protein contains a putative nuclear-localizing sequence. This finding indicates that leukotrienes may even act as intracellular messengers.