Downregulation of caspases and Fas ligand expression, and increased lifespan of neutrophils after transmigration across intestinal epithelium.

During inflammatory bowel diseases, commitment of extravased polymorphonuclear leucocytes (PMN) to apoptosis is required for the resolution of inflammation. To investigate the effect of transepithelial migration on PMN apoptotic rates, PMN transepithelial migration was reproduced in vitro using T84 intestinal monolayers. Transepithelial migration was found to delay neutrophil apoptosis, and this survival effect correlated with a downregulation of the surface expression of Fas ligand (FasL) and with a decrease in both procaspases-3, and -8 mRNA and procaspases-3, -6, -7 and -8 protein levels. Moreover, neutrophil survival and FasL shedding mediated by transepithelial migration were abrogated by a broad-spectrum metalloproteinase inhibitor, BB-94. Although Erk1/2 and p38 MAPK were activated in transmigrated PMN, inhibition of these MAP kinases did not impair transmigration-induced PMN survival. Taken together, our results show that trans-epithelial migration induces the downregulation of proapoptotic proteins expression in transmigrated PMN, which results in their increased lifespan.