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Identification of a Human Enterocyte Lipoxin A₄ Receptor That Is Regulated by Interleukin (IL)-13 and Interferon and Inhibits Tumor Necrosis Factor –induced IL-8 Release

Karsten Gronert^*, Andrew Gewirtz, James L. Madara, and Charles N. Serhan^*

From the ^* Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, and the Division of Gastrointestinal Pathology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

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 were the most potent. When lipoxins and LXA₄ stable analogs were evaluated for enterocyte functional as well as immune responses, lipoxins sharply inhibited TNF-–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 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-1β– and TNF-–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.

¹Abbreviations used in this paper: 15-epi-LXA₄, 5(S),6(R),15(R)-trihydroxy-7,9,13-trans-11-cis eicosatetraenoic acid; 15 (R/S)-methyl LXA₄, 5(S),6(R), 15(R/S)-trihydroxy-15-methyl-7,9,13-trans-11-cis-eicosatetraenoic acid; 16-phenoxy-LXA₄, 16-phenoxy-17,18,19,20-tetranor-LXA₄; aspirin, acetylsalicylic acid; COX, cyclooxygenase (PGHS); 15-HETE, 15-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid; LO, lipoxygenase; LXA₄, 5(S),6(R),15(S)-trihydroxy-7,9,13-trans-11-cis eicosatetraenoic acid; LXA₄R, lipoxin A₄ receptor; RP-HPLC, reverse phase-HPLC.

The present address of Drs. Gewirtz and Madara is Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.

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