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Research Article Free access | 10.1172/JCI1339

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

A T Gewirtz, B McCormick, A S Neish, N A Petasis, K Gronert, C N Serhan, and J L Madara

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. agewirt@emory.edu

Find articles by Gewirtz, A. in: PubMed | Google Scholar

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. agewirt@emory.edu

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Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. agewirt@emory.edu

Find articles by Neish, A. in: PubMed | Google Scholar

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. agewirt@emory.edu

Find articles by Petasis, N. in: PubMed | Google Scholar

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. agewirt@emory.edu

Find articles by Gronert, K. in: PubMed | Google Scholar

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. agewirt@emory.edu

Find articles by Serhan, C. in: PubMed | Google Scholar

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA. agewirt@emory.edu

Find articles by Madara, J. in: PubMed | Google Scholar

Published May 1, 1998 - More info

Published in Volume 101, Issue 9 on May 1, 1998
J Clin Invest. 1998;101(9):1860–1869. https://doi.org/10.1172/JCI1339.
© 1998 The American Society for Clinical Investigation
Published May 1, 1998 - Version history
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Abstract

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 A4 (LXA4) 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 LXA4. 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 LXA4 inhibited S. typhimurium-induced (but not phorbol ester-induced) secretion of both IL-8 and pathogen-elicited epithelial chemoattractant. LXA4 stable analogs did not alter bacterial adherence to nor internalization by epithelia, indicating that LXA4 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 LXA4 analogs was concentration- (IC50 approximately 1 nM) and time-dependent (maximal inhibition approximately 1 h). As a result of these effects, LXA4 stable analogs inhibited the ability of bacteria-infected epithelia to direct polymorphonuclear leukocyte movement. These data suggest that LXA4 and its stable analogs may be useful in downregulating active inflammation at mucosal surfaces.

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