Pathogen-induced chemokine secretion from model intestinal epithelium is inhibited by lipoxin A4 analogs

Enteric pathogens induce intestinal epithelium to secrete chemokines that direct movement of polymorphonuclear leukocytes. Mechanisms that might downregulate secretion of these proinflammatory chemokines and thus contain intestinal inflammation have not yet been elucidated. The antiinflammatory activities exhibited by the arachidonate metabolite lipoxin A(4) (LXA(4)) suggests that this eicosanoid, which is biosynthesized in vivo at sites of inflammation, might play such a role. We investigated whether chemokine secretion could be regulated by stable analogs of LXA(4). Monolayers of T84 intestinal epithelial cells were infected with Salmonella typhimurium, which elicits secretion of distinct apical (pathogen-elicited epithelial chemoattractant) and basolateral (IL-8) chemokines. Stable analogs of LXA(4) inhibited S. typhimurium-induced (but not phorbol ester-induced) secretion of both IL-8 and pathogen-elicited epithelial chemoattractant. LXA(4) stable analogs did not alter bacterial adherence to nor internalization by epithelia, indicating that LXA(4) stable analogs did not block all signals that Salmonella typhimurium activates in intestinal epithelia, but likely led to attenuation of signals that mediate chemokine secretion. Inhibition of S. typhimurium-induced IL-8 secretion by LXA(4) analogs was concentration-(IC50 similar to 1 nM) and time-dependent (maximal inhibition similar to 1 h). As a result of these effects, LXA(4) stable analogs inhibited the ability of bacteria-infected epithelia to direct polymorphonuclear leukocyte movement. These data suggest that LXA(4) and its stable analogs may be useful in downregulating active inflammation at mucosal surfaces.