Lipoxin a4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfate-induced colitis.
The anti-inflammatory eicosanoid lipoxin A(4) (LXA(4)), aspirin-triggered 15-epi-LXA(4), 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. LXA(4) analog alone did not significantly affect expression of any of the >7000 genes analyzed. However, LXA(4) analog pretreatment attenuated induction of approximately 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 LXA(4) analog pretreatment is regulated by NF-kappaB, suggesting that LXA(4) analog was influencing the activity of this transcription factor. Nanomolar concentrations of LXA(4) analog reduced NF-kappaB-mediated transcriptional activation in a LXA(4) receptor-dependent manner and inhibited induced degradation of IkappaBalpha. LXA(4) analog did not affect earlier stimulus-induced signaling events that lead to IkappaBalpha degradation, such as S. typhimurium-induced epithelial Ca(2+) mobilization or TNF-alpha-induced phosphorylation of IkappaBalpha. To establish the in vivo relevance of these findings, we examined whether LXA(4) analogs could affect intestinal inflammation in vivo using the mouse model of DSS-induced inflammatory colitis. Oral administration of LXA(4) analog (15-epi-16-para-fluoro-phenoxy-LXA(4), 10 microg/day) significantly reduced the weight loss, hematochezia, and mortality that characterize DSS colitis. Thus, LXA(4) analog-mediated down-regulation of proinflammatory gene expression via inhibition of the NF-kappaB pathway can be therapeutic for diseases characterized by mucosal inflammation.
Gewirtz
Andrew T
AT
Department of Pathology and Laboratory Medicine, Emory University, WRB 10SH, 6125 Michael Street, Atlanta, GA 30322, USA. agewirt@emory.edu
Collier-Hyams
Lauren S
LS
Young
Andrew N
AN
Kucharzik
Torsten
T
Guilford
William J
WJ
Parkinson
John F
JF
Williams
Ifor R
IR
Neish
Andrew S
AS
Madara
James L
JL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D044045:Lipoxins; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D012486:Salmonella typhimurium / Q000276:immunology; D012720:Severity of Illness Index
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006893:Hydroxyeicosatetraenoic Acids; D044045:Lipoxins; C040527:lipoxin A4; D016264:Dextran Sulfate