The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1285/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 8, April 20, 1998 1285-1294

Articles

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

Karsten Gronert*, Andrew Gewirtz{ddagger}, James L. Madara{ddagger}, and Charles N. Serhan*

From the * Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesia, and the {ddagger} 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 {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 ~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-{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.

Address correspondence to Charles N. Serhan, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St., Boston, MA 02115. Phone: 617-732-8822; Fax: 617-278-6957; E-mail: cnserhan{at}zeus.bwh.harvard.edu

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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