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Originally published In Press as doi:10.1074/jbc.M104942200 on September 26, 2001

J. Biol. Chem., Vol. 276, Issue 48, 44464-44471, November 30, 2001
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Signal Transduction Pathways Mediating Neurotensin-stimulated Interleukin-8 Expression in Human Colonocytes*

Dezheng Zhao, Andrew C. KeatesDagger , Sabina Kuhnt-Moore, Mary P. Moyer§, Ciaran P. Kelly, and Charalabos Pothoulakis

From the Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 and § INCELL Corporation, San Antonio, Texas 78249

Neurotensin (NT), a neuropeptide released in the gastrointestinal tract in response to several stimuli, is involved in the pathophysiology of colonic inflammation. However, the molecular mechanism(s) mediating this proinflammatory response remains unclear. We found that NCM460, non-transformed human colonocytes, express a functional high affinity NT receptor that mediates NT-induced Erk activation. By using NCM460 cells stably transfected with NTR1, we show that NTR1 activation leads to interleukin (IL)-8 secretion that is mediated via both NF-kappa B- and Erk-dependent pathways. In addition, NT-stimulated NF-kappa B activation is dependent on intracellular calcium release. NT-stimulated Erk activity requires Ras activation because overexpression of the dominant negative Ras mutant Ras-17N almost completely inhibits the Erk activation. Furthermore, NT directly stimulates Ras-GTP formation as shown by a Ras-GTP pull-down assay. By using reporter gene constructs containing targeted substitutions in the IL-8 promoter, we show that the NF-kappa B, AP-1, and to a lesser degree the C/EBP sites in the IL-8 promoter region are required for IL-8 gene expression induced by NT. In summary, our results demonstrate that NT stimulates calcium-dependent NF-kappa B and Ras-dependent Erk pathways that mediate the release of IL-8 from non-transformed human colonocytes. We speculate that these NT-related proinflammatory pathways are important in the pathophysiology of colonic inflammation.

* This work was supported in part by National Institutes of Health Grants DK 33506 (to C. P.) and DK54920 (to C. P. K.) and by the Crohn's and Colitis Foundation of America.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Recipient of Career Development award from the Crohn's and Colitis Foundation of America.

To whom correspondence should be addressed: Beth Israel Deaconess Medical Center, Division of Gastroenterology, Dana 501, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-1259; Fax: 617-667-5071; E-mail: cpothoul@caregroup.harvard.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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