Influence of leukotriene D4 and cyclooxygenase-2 on cell survival

Abstract: The pro-inflammatory effect of leukotrienes is an important element in the pathogenesis of multiple disorders, including asthma and inflammatory bowel diseases (IBD). A serious concern for IBD patients is the increased risk of developing colorectal cancer and since there seems to be a general connection between inflammation and cancer we hypothesised that LTD4 induced signalling events could be involved in increasing the tumourgenic potential of cells. Another important player in colorectal carcinogenesis, as well as in inflammation is the inducible cyclooxygenase isoform COX-2. Inhibition of this enzyme reduces cancer risk and it is highly elevated in tumour tissue. We treated non-transformed intestinal epithelial cells with LTD4 and found that this led to increased expression of COX-2. Additionally, the anti-apoptotic protein Bcl-2 was elevated prompting us to study the effect of LTD4 on survival and apoptosis. We could show that inhibition of COX-2 causes increased apoptosis, mediated through activation of caspase-8, cleavage of Bid and mitochondrial release of cytochrome c. All these events could be reversed by the addition of LTD4, which even could increase cell survival above basal level. We furthermore detected a novel LTD4-induced association between Bcl-2 and the multifacetted protein b-catenin that may encompass a new mode of influencing cell survival. These effects of LTD4 were shown to be mediated through the G-protein coupled receptor, CysLT1 and this strongly indicates that inflammatory mediators such as LTD4 may have large impacts on the state of cell survival regulation.