Neurotensin stimulates IL-8 expression in human colonic epithelial cells through Rho GTPase-mediated NF-kappa B pathways |
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Authors: | Zhao Dezheng Kuhnt-Moore Sabina Zeng Huiyan Wu Jack S Moyer Mary P Pothoulakis Charalabos |
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Affiliation: | Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02468, USA. |
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Abstract: | Neurotensin (NT), a neuropeptide highlyexpressed in the gastrointestinal tract, participates in thepathophysiology of intestinal inflammation. We recently showed that NTstimulates interleukin-8 (IL-8) expression in NCM460 nontransformedhuman colonic epithelial cells via both mitogen-activating proteinkinase (MAPK)- and NF-B-dependent pathways. However, the molecularmechanism by which NT induces expression of proinflammatory cytokinessuch as IL-8 has not been investigated. In this study we show thatinhibition of endogenous Rho family proteins (RhoA, Rac1, and Cdc42) bytheir respective dominant negative mutants inhibits NT-induced IL-8protein production and promoter activity. Western blot experimentsdemonstrated that NT strongly activated RhoA, Rac1, and Cdc42.Overexpression of the dominant negative mutants of RhoA, Rac1, andCdc42 significantly inhibited NT-induced NF-B-dependent reportergene expression and NF-B DNA binding activity. NT also stimulatedp38 MAPK phosphorylation, and overexpression of dominant negativemutants of RhoA, Rac1, and Cdc42 did not significantly alter p38 andERK1/2 phosphorylation in response to NT. Together, our findingsindicate that NT-stimulated IL-8 expression is mediated via aRho-dependent NF-B-mediated pathway. |
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