title: Identification of a human enterocyte lipoxin A4 receptor that is regulated by interleukin (IL)-13 and interferon gamma and inhibits tumor necrosis factor alpha-induced IL-8 release.
abstract: Epithelial cells of the alimentary tract play a central role in mucosal immunophysiology. Pathogens and/or agonists that interact with mucosal surfaces often elicit epithelial responses that upregulate inflammation. Therefore, it was of interest to explore potential epithelial targeted antiinflammatory signals. Here we identified and sequenced a human enterocyte lipoxin (LX) A4 [5(S), 6(R),15(S)-trihydroxy-7,9,13-trans-11-cis eicosatetraenoic acid] receptor, and demonstrate that transcription of this receptor was controlled by cytokines, of which lymphocyte-derived interleukin (IL)-13 and interferon gamma were the most potent. When lipoxins and LXA4 stable analogs were evaluated for enterocyte functional as well as immune responses, lipoxins sharply inhibited TNF-alpha-induced IL-8 release but did not alter either barrier function or agonist-stimulated chloride secretion. 15R/S-methyl-LXA4 and 16-phenoxy-LXA4 each attenuated (IC50 approximately 10 nM) IL-8 release. Cyclooxygenase (COX) II is emerging as an important component in wound healing and proliferation in intestinal epithelia and when acetylated by acetylsalicylic acid (aspirin) initiates the biosynthesis of a LXA4 receptor ligand. We therefore determined whether colonic cell lines (HT-29 Cl.19A, Caco-2, or T84) express the COX II isozyme. Results for RT-PCR and Western blot analysis showed that COX I as well as an IL-1beta- and TNF-alpha-inducible COX II are expressed in HT-29 Cl.19A. In addition, aspirin-treated enterocytes generated 15R-HETE, a precursor of 15-epi-LXA4 biosynthesis, whose potent bioactions were mimicked by the stable analog 15R/S-methyl-LXA4. Taken together, these results identify an endogenous pathway for downregulating mucosal inflammatory events and suggest a potential therapeutic benefit for LXA4 stable analogs.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: K
authors.initials: K
authors.lastname: Gronert
authors.forename: A
authors.initials: A
authors.lastname: Gewirtz
authors.forename: J L
authors.initials: JL
authors.lastname: Madara
authors.forename: C N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D001241:Aspirin / Q000494:pharmacology; D018938:Caco-2 Cells; D003001:Cloning, Molecular; D051546:Cyclooxygenase 2; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007527:Isoenzymes; D044045:Lipoxins; D008565:Membrane Proteins; D018448:Models, Immunological; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C105101:FPR2 protein, human; D006893:Hydroxyeicosatetraenoic Acids; D018793:Interleukin-13; D016209:Interleukin-8; D007527:Isoenzymes; D044045:Lipoxins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin