PATHOGEN-INDUCED CHEMOKINE SECRETION FROM MODEL INTESTINAL EPITHELIUMIS INHIBITED BY LIPOXIN A(4) ANALOGS

Enteric pathogens induce intestinal epithelium to secrete chemokines t hat direct movement of polymorphonuclear leukocytes. Mechanisms that m ight downregulate secretion of these proinflammatory chemokines and th us contain intestinal inflammation have not yet been elucidated. The a ntiinflammatory activities exhibited by the arachidonate metabolite li poxin A(4) (LXA(4)) suggests that this eicosanoid, which is biosynthes ized in vivo at sites of inflammation, might play such a role. We inve stigated whether chemokine secretion could be regulated by stable anal ogs of LXA(4). Monolayers of T84 intestinal epithelial cells were infe cted 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-i nduced (but not phorbol ester-induced) secretion of both IL-8 and path ogen-elicited epithelial chemoattractant. LXA(4) stable analogs did no t alter bacterial adherence to nor internalization by epithelia, indic ating that LXA(4) stable analogs did not block all signals that Salmon ella 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 concentra tion-(IC50 similar to 1 nM) and time-dependent (maximal inhibition sim ilar to 1 h). As a result of these effects, LXA(4) stable analogs inhi bited the ability of bacteria-infected epithelia to direct polymorphon uclear leukocyte movement. These data suggest that LXA(4) and its stab le analogs may be useful in downregulating active inflammation at muco sal surfaces.