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J. Biol. Chem., Vol. 279, Issue 44, 45519-45527, October 29, 2004

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Metalloproteinases and Transforming Growth Factor- Mediate Substance P-induced Mitogen-activated Protein Kinase Activation and Proliferation in Human Colonocytes^*

Hon-Wai Koon, Dezheng Zhao, Xi Na, Mary P. Moyer, and Charalabos Pothoulakis¶

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

Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of proinflammatory cytokines from colonic epithelial cells. SP also stimulates cell proliferation, a critical event in tissue healing during chronic colitis, via transactivation of the epidermal growth factor (EGF) receptor (EGFR) and activation of mitogen-activated protein kinase (MAPK). Here we examined the mechanism by which SP induces EGFR and MAPK activation. We used non-transformed human NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) as well as untransfected U373 MG cells expressing high levels of endogenous NK-1R. Exposure of both cell lines to SP (10^–7 M) stimulated EGFR activation (1 min) followed by extracellular signal-regulated protein kinase (ERK1/2) activation (2–5 min). SP-induced ERK1/2 activation was blocked by pretreatment with the metalloproteinase inhibitor Batimastat/GM6001, the EGFR phosphorylation inhibitor AG1478, and the tumor necrosis factor--converting enzyme (TACE) inhibitor TAPI-1. Pretreatment with antibodies against potential EGFR ligands suggested that transforming growth factor- (TGF), but not the other EGFR ligands EGF, heparin-binding EGF, or amphiregulin, mediates SP-induced EGFR transactivation. SP stimulated TGF release into the extracellular space that was measurable within 2 min, and this release was inhibited by metalloproteinase inhibitors and the TACE inhibitor TAPI-1. SP also induced MAPK-mediated cell proliferation that was inhibited by TACE, matrix metalloproteinase (MMP), EGFR, and MEK1 inhibitors. Thus, in human colonocytes, NK-1R-induced EGFR and MAPK activation and cell proliferation involve matrix metalloproteinases (most likely TACE) and the release of TGF. These signaling mechanisms may be involved in the protective effects of NK-1R in chronic colitis.

Received for publication, July 27, 2004

^* This work was supported by National Institutes of Health Grant DK 47343 (to C. P.). 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.

^¶ 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: 617-667-2767; E-mail: cpothoul{at}bidmc.harvard.edu.

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