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* Department of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital, Boston, MA 02129;
Department of Microbiology & Molecular Genetics, Harvard Medical School, Boston, MA 02115;
University of California, Berkeley, Center for Eye Disease and Development, School of Optometry, Berkeley, CA 94720;
Department of Pharmacy & Pharmacology, University of Bath, Bath, United Kingdom; and
¶ Unity Pharmaceuticals, Menlo Park, CA 94025
Neutrophil transmigration across mucosal surfaces contributes to dysfunction of epithelial barrier properties, a characteristic underlying many mucosal inflammatory diseases. Thus, insight into the directional movement of neutrophils across epithelial barriers will provide important information relating to the mechanisms of such inflammatory disorders. The eicosanoid hepoxilin A3, an endogenous product of 12-lipoxygenase activity, is secreted from the apical surface of the epithelial barrier and establishes a chemotactic gradient to guide neutrophils from the submucosa across epithelia to the luminal site of an inflammatory stimulus, the final step in neutrophil recruitment. Currently, little is known regarding how hepoxilin A3 is secreted from the intestinal epithelium during an inflammatory insult. In this study, we reveal that hepoxilin A3 is a substrate for the apical efflux ATP-binding protein transporter multidrug resistance-associated protein 2 (MRP2). Moreover, using multiple in vitro and in vivo models, we show that induction of intestinal inflammation profoundly up-regulates apical expression of MRP2, and that interfering with hepoxilin A3 synthesis and/or inhibition of MRP2 function results in a marked reduction in inflammation and severity of disease. Lastly, examination of inflamed intestinal epithelia in human biopsies revealed up-regulation of MRP2. Thus, blocking hepoxilin A3 synthesis and/or inhibiting MRP2 may lead to the development of new therapeutic strategies for the treatment of epithelial-associated inflammatory conditions.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by National Institutes of Health Grants DK 56754 and DK 33506 (to B.A.M.), National Eye Institute Grant EY01613604 (to K.G.), and a T32 Training Grant sponsored by Harvard Medical School and the Department of Surgery at Massachusetts General Hospital (to K.L.M.). M.P. was supported by a National Institutes of Health Minority Supplement Award.
2 Address correspondence and reprint requests to Dr. Beth A. McCormick, Massachusetts General Hospital, CNY 114 16th Street (3503), Charlestown, MA 02129. E-mail address: mccormic{at}helix.mgh.harvard.edu
3 Abbreviations used in this paper: PMN, polymorphonuclear neutrophil; HXA3, hepoxilin; LOX, lipoxygenase; ABC, ATP-binding cassette; MRP, multidrug resistance-associated protein; MDR, multidrug resistance; IBD, inflammatory bowel disease; siRNA, small interfering RNA; 12S-HpETE, hydroperoxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid; 12-HETE, 12-Hydroxyeicosatetraenoic acid; LC/MS/MS, liquid chromatography/mass spectrometry/mass spectrometry.
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