title: 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.
abstract: 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-LXA(4)) may contribute to the bioactivity profile of this prototype nonsteroidal anti-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 stable analogs of LXA(4) on TNF-alpha-stimulated neutrophil-enterocyte interaction in vitro and TNF-alpha-stimulated chemokine release, changes in mucosal architecture, and enterocyte apoptosis in cytokine-activated intact human 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)) inhibited 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 protein-1 (MCP-1) and RANTES. Exposure of strips of normal human colonic mucosa to TNF-alpha 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-LXA(4) attenuated TNF-alpha-stimulated colonocyte apoptosis and protected the mucosa against TNF-alpha-induced mucosal damage. In aggregate, our data demonstrate that lipoxins and aspirin-triggered 15-epi-LXA(4) are potent antagonists of TNF-alpha-mediated neutrophil-enterocyte interactions in vitro, attenuate TNF-alpha-triggered chemokine release and colonocyte apoptosis, and are protective against TNF-alpha-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.
authors.affiliation: Department of Gastroenterology, Mater Misericordiae Hospital, Dublin, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Goh
authors.forename: A W
authors.initials: AW
authors.lastname: Baird
authors.forename: C
authors.initials: C
authors.lastname: O'Keane
authors.forename: R W
authors.initials: RW
authors.lastname: Watson
authors.forename: D
authors.initials: D
authors.lastname: Cottell
authors.forename: G
authors.initials: G
authors.lastname: Bernasconi
authors.forename: N A
authors.initials: NA
authors.lastname: Petasis
authors.forename: C
authors.initials: C
authors.lastname: Godson
authors.forename: H R
authors.initials: HR
authors.lastname: Brady
authors.forename: P
authors.initials: P
authors.lastname: MacMathuna
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000494:pharmacology; D002460:Cell Line; D018932:Chemokine CCL2 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000096:biosynthesis; D018925:Chemokines / Q000096:biosynthesis; D020895:Enterocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D044045:Lipoxins; D008854:Microscopy, Electron; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D018925:Chemokines; D006893:Hydroxyeicosatetraenoic Acids; D016209:Interleukin-8; D044045:Lipoxins; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D001241:Aspirin