Lipoxin A(4) and aspirin-triggered 15-epi-lipoxin A(4) antagonize TNF-alpha-stimulated neutrophil-enterocyte interactions in vitro and attenuate TNF-alpha-induced chemokine release and colonocyte apoptosis in human intestinal mucosa ex vivo

Lipoxins (LXs) are lipoxygenase-derived eicosanoids and putative endogenous braking signals for inflammation in the gastrointestinal tract and other o rgans. Aspirin triggers the production of 15-epimers during cell-cell inter action 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-LXA(4)) may contribute to the bioactivity profile of this prototype nonsteroidal an ti-inflammatory drug in vivo. We determined the effect of LXA(4), 15-(R/S)- methyl-11,12-dehydro-LXA(4) methyl ester (15-(R/S)-methyl-LXA(4)), and stab le analogs of LXA(4) on TNF-alpha -stimulated neutrophil-enterocyte interac tion in vitro and TNF-alpha -stimulated chemokine release, changes in mucos al architecture, and enterocyte apoptosis in cytokine-activated intact huma n colonic mucosa ex vivo. LXA(4), 15-(R/S)-epi-LXA(4), and 16-phenoxy-11,12 -dehydro-17,18,19,20-tetranor-LXA(4) methyl ester (16-phenoxy-LXA(4)) inhib ited TNF-alpha -stimulated neutrophil adherence to epithelial monolayers at nanomolar concentrations. In parallel experiments involving human colonic mucosa ex vivo, LXA(4)potently attenuated TNF-alpha -stimulated release of the C-X-C chemokine IL-8, and the C-C chemokines monocyte-chemoattractant p rotein-1 (MCP-1) and RANTES. Exposure of strips of normal human colonic muc osa to TNF-alpha induced disruption of mucosa architecture and enhanced col onocyte apoptosis via a caspase-3-independent mechanism. Prior exposure of the mucosa strips to 15-(RIS)-methyl-LXA(4) attenuated TNF-alpha -stimulate d colonocyte apoptosis and protected the mucosa against TNF-alpha -induced mucosal damage. In aggregate, our data demonstrate that lipoxins; and aspir in-triggered 15-epi-LXA(4) are potent antagonists of TNF-alpha -mediated ne utrophil-enterocyte interactions in vitro, attenuate TNF-alpha -triggered c hemokine release and colonocyte apoptosis, and are protective against TNF-a lpha -induced morphological disruption in human colonic strips ex vivo. Our observations further expand the anti-inflammatory profile of these lipoxyg enase-derived eicosanoids and suggest new therapeutic approaches for the tr eatment of inflammatory bowel disease.