Regulation of survival and proliferation of human intestinal epithelial cells by leukotriene D4

Abstract: The pro-inflammatory mediator, Leukotriene D4 (LTD4) is a product of arachidonic acid cascade and has been implicated in asthma and inflammatory bowel diseases. Prolonged inflammatory conditions like ulcerative colitis increases the risk for the development of cancer and the factors that induce the chronic immune response remain uncertain. In this context, in the present study, we examined if exposure of non-transformed intestinal cells to LTD4, a well known inflammatory mediator would make the cells more sensitive to transformation. We investigated the effects of LTD4 in bringing about changes in survival, proliferation and migration of these cells, all of which are hallmarks of cancer. We observed that stimulation of intestinal epithelial cell line, Int 407 with LTD4 led to enhanced cell survival, proliferation and migration through activation of series of signaling cascades like Ras, Erk-1/2, p90RSK, and CREB. These effects are believed to be mediated through CysLT1 receptor as CysLT1 receptor antagonist could effectively block these changes. We also show that Int 407 cells produce CysLT and blocking this autocrine signaling using three different CysLT1 receptor antagonists for longer time points led to attenuation in cell proliferation and induction of apoptosis in the cells. This suggest that LTD4 signaling through CysLT1 receptor is some how crucial for normal maintenance of intestinal epithelial cells. LTD4 stimulation also led to significant enhancement of cell migration in a PI3K and Rac-dependent manner. All these results indicate that this inflammatory mediator could be implicated in the inflammation-induced neoplastic transformation through CysLT1R and the downstream signaling cascades.