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Neurotensin Stimulates Interleukin-8 Expression through Modulation of IB Phosphorylation and p65 Transcriptional Activity: Involvement of Protein Kinase C

Division of Gastroenterology (D.Z., Y.Z., H.W.K., C.P.) and Department of Pathology (H.Z.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and INCELL Corporation, San Antonio, Texas (M.P.M.)

Neurotensin (NT) is released in the gastrointestinal tract and participates in the pathophysiology of colonic inflammation. We have shown that NT mediates acute intestinal inflammation in vivo and stimulates nuclear factor-B–dependent interleukin (IL)-8 expression in nontransformed human colonocytes in vitro. However, the exact mechanisms by which NT induces IL-8 expression have not been elucidated. In this study, we first show that NT stimulates IB phosphorylation and degradation and p65 phosphorylation and transcriptional activity. Inhibition of protein kinase C (PKC) activation significantly attenuates NT-induced IL-8 expression. This effect seems to be mediated through inhibition of IB phosphorylation and degradation and by p65 phosphorylation and transcriptional activity. We also show that intracellular calcium mobilization is necessary for NT-induced phosphorylation of IB and p65, suggesting that a conventional PKC is involved. Furthermore, transfection of a dominant-negative form of PKC significantly reduces NT-induced IL-8 promoter activity. These results indicate that the conventional PKC is an important mediator in the proinflammatory signaling pathway elicited by NT at the colonocyte level.

Address correspondence to: Dr. Charalabos Pothoulakis, Beth Israel Deaconess Medical Center, Gastrointestinal Neuropeptide Center, Division of Gastroenterology, Dana 601, 330 Brookline Avenue, Boston, MA 02215. E-mail: cpothoul{at}bidmc.harvard.edu

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