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* Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322; and
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-
B, suggesting that
LXA4 analog was influencing the activity of this
transcription factor. Nanomolar concentrations of LXA4
analog reduced NF-B-mediated transcriptional activation in a
LXA4 receptor-dependent manner and inhibited induced
degradation of IB
. LXA4 analog did not affect earlier
stimulus-induced signaling events that lead to IB degradation,
such as S. typhimurium-induced epithelial
Ca2+ mobilization or TNF--induced phosphorylation of
IB. 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-B pathway can be therapeutic for diseases characterized by
mucosal inflammation.
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