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-Stimulated Neutrophil-Enterocyte Interactions In Vitro and Attenuate TNF--Induced Chemokine Release and Colonocyte Apoptosis in Human Intestinal Mucosa Ex Vivo1
,,
Departments of
*
Gastroenterology, and
Medicine and Therapeutics, Mater Misericordiae Hospital, and
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, and the Dublin Molecular Medicine Centre, Dublin, Ireland; and
Department of Chemistry, University of Southern California, Los Angeles, CA 90089
Lipoxins (LXs) are lipoxygenase-derived eicosanoids and putative
endogenous braking signals for inflammation in the gastrointestinal
tract and other organs. Aspirin triggers the production of 15-epimers
during cell-cell interaction in a cytokine-primed milieu, and
aspirin-triggered
15-epi-5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic
acid (15-epi-LXA4) may contribute to the bioactivity
profile of this prototype nonsteroidal anti-inflammatory drug in
vivo. We determined the effect of LXA4,
15-(R/S)-methyl-11,12-dehydro-LXA4 methyl
ester (15-(R/S)-methyl-LXA4), and stable
analogs of LXA4 on TNF-
-stimulated neutrophil-enterocyte
interaction in vitro and TNF--stimulated chemokine release, changes
in mucosal architecture, and enterocyte apoptosis in cytokine-activated
intact human colonic mucosa ex vivo. LXA4,
15-(R/S)-epi-LXA4, and
16-phenoxy-11,12-dehydro-17,18,19,20-tetranor-LXA4 methyl
ester (16-phenoxy-LXA4) inhibited TNF--stimulated
neutrophil adherence to epithelial monolayers at nanomolar
concentrations. In parallel experiments involving human colonic mucosa
ex vivo, LXA4potently attenuated TNF--stimulated release
of the C-X-C chemokine IL-8, and the C-C chemokines
monocyte-chemoattractant protein-1 (MCP-1) and RANTES. Exposure of
strips of normal human colonic mucosa to TNF- induced disruption of
mucosa architecture and enhanced colonocyte apoptosis via a
caspase-3-independent mechanism. Prior exposure of the mucosa strips to
15-(R/S)-methyl-LXA4 attenuated
TNF--stimulated colonocyte apoptosis and protected the mucosa
against TNF--induced mucosal damage. In aggregate, our data
demonstrate that lipoxins and aspirin-triggered 15-epi-LXA4
are potent antagonists of TNF--mediated neutrophil-enterocyte
interactions in vitro, attenuate TNF--triggered chemokine release
and colonocyte apoptosis, and are protective against TNF--induced
morphological disruption in human colonic strips ex vivo. Our
observations further expand the anti-inflammatory profile of these
lipoxygenase-derived eicosanoids and suggest new therapeutic approaches
for the treatment of inflammatory bowel disease.
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