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The Journal of Immunology, 2002, 168: 5260-5267.
Copyright © 2002 by The American Association of Immunologists

Lipoxin A4 Analogs Attenuate Induction of Intestinal Epithelial Proinflammatory Gene Expression and Reduce the Severity of Dextran Sodium Sulfate-Induced Colitis1

Andrew T. Gewirtz2,*, Lauren S. Collier-Hyams*, Andrew N. Young*, Torsten Kucharzik*, William J. Guilford{dagger}, John F. Parkinson{dagger}, Ifor R. Williams*, Andrew S. Neish* and James L. Madara*

* Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; and {dagger} Departments of Medicinal Chemistry and Immunology, Berlex Biosciences, Richmond, CA 94804

The anti-inflammatory eicosanoid lipoxin A4 (LXA4), aspirin-triggered 15-epi-LXA4, and their stable analogs down-regulate IL-8 secretion and subsequent recruitment of neutrophils by intestinal epithelia. In an effort to elucidate the mechanism by which these lipid mediators modulate cellular proinflammatory programs, we surveyed global epithelial gene expression using cDNA microarrays. LXA4 analog alone did not significantly affect expression of any of the >7000 genes analyzed. However, LXA4 analog pretreatment attenuated induction of ~50% of the 125 genes up-regulated in response to the gastroenteritis-causing pathogen Salmonella typhimurium. A major subset of genes whose induction was reduced by LXA4 analog pretreatment is regulated by NF-{kappa}B, suggesting that LXA4 analog was influencing the activity of this transcription factor. Nanomolar concentrations of LXA4 analog reduced NF-{kappa}B-mediated transcriptional activation in a LXA4 receptor-dependent manner and inhibited induced degradation of I{kappa}B{alpha}. LXA4 analog did not affect earlier stimulus-induced signaling events that lead to I{kappa}B{alpha} degradation, such as S. typhimurium-induced epithelial Ca2+ mobilization or TNF-{alpha}-induced phosphorylation of I{kappa}B{alpha}. To establish the in vivo relevance of these findings, we examined whether LXA4 analogs could affect intestinal inflammation in vivo using the mouse model of DSS-induced inflammatory colitis. Oral administration of LXA4 analog (15-epi-16-para-fluoro-phenoxy-LXA4, 10 µg/day) significantly reduced the weight loss, hematochezia, and mortality that characterize DSS colitis. Thus, LXA4 analog-mediated down-regulation of proinflammatory gene expression via inhibition of the NF-{kappa}B pathway can be therapeutic for diseases characterized by mucosal inflammation.




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