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Am J Physiol Cell Physiol (February 12, 2003). doi:10.1152/ajpcell.00328.2002
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Submitted on July 12, 2002
Accepted on January 22, 2003

Neurotensin stimulates interleukin-8 expression in human colonic epithelial cells through Rho GTPase-mediated NF{kappa}B pathways

Dezheng Zhao1, Sabina Kuhnt-Moore2, Huiyan Zeng3, Jack S Wu1, Mary P Moyer1, and Charalabos Pothoulakis1*

1 Medicine, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA
2 Medicine, Beth Israel Deaconess Medical Center Harvard Harvard Medical School, Boston, MA, USA
3 Pathology, Beth Israel Deaconess Medical Center Harvard Harvard Medical School, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: cpothoul{at}caregroup.harvard.edu.

Neurotensin (NT), a neuropeptide highly expressed in the gastrointestinal tract, participates in the pathophysiology of intestinal inflammation. We recently showed that NT stimulates interleukin-8 (IL-8) expression in NCM460 non-transformed human colonic epithelial cells via both mitogen-activated protein kinase and NF-{kappa}B-dependent pathways. However the molecular mechanism by which NT induces expression of proinflammatory cytokines such as IL-8 has not been investigated. In this study we show that inhibition of endogenous Rho family proteins (RhoA, Rac1 and Cdc42) by their respective dominant negative mutants inhibits NT-induced IL-8 protein production and promoter activity. Western blot experiments demonstrated that NT strongly activated RhoA, Rac1 and Cdc42. Overexpression of the dominant negative mutants of RhoA, Rac1 and Cdc42 significantly inhibited NT-induced NF-{kappa}B dependent reporter gene expression and NF-{kappa}B DNA binding activity. NT also stimulated p38 MAP kinase phosphorylation and overexpression of dominant negative mutants of RhoA, Rac1, and Cdc42 did not significantly alter p38 and Erk1/2 phosphorylation in response to NT. Taken together, our findings indicate that NT-stimulated IL-8 expression is mediated via a Rho-dependent NF-{kappa}B-mediated pathway.




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