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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 25, 2005; DOI: 10.1124/jpet.105.088013

0022-3565/05/3143-1393-1400$20.00
JPET 314:1393-1400, 2005
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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Substance P-Stimulated Interleukin-8 Expression in Human Colonic Epithelial Cells Involves Protein Kinase C{delta} Activation

Hon-Wai Koon, Dezheng Zhao, Yanai Zhan, Simos Simeonidis, Mary P. Moyer, and Charalabos Pothoulakis

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

Substance P (SP) participates in acute intestinal inflammation via binding to the G-protein-coupled neurokinin-1 receptor (NK-1R) and release of nuclear factor {kappa} B (NF-{kappa}B)-driven proinflammatory cytokines from colonic epithelial cells. However, the signal transduction pathways by which SP-NK-1R interaction induces NF-{kappa}B activation and interleukin-8 (IL-8) production are not clear. Here, we examined participation of protein kinase C (PKC) in SP-induced IL-8 production in human nontransformed NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells). SP (10-7 M) induced an early (1 min) phosphorylation of the PKC isoforms PKC{delta}, PKC{theta}, and PKC{epsilon}, followed by I-{kappa}B kinase, I{kappa}B{alpha}, and p65 phosphorylation. Depletion of PKC by phorbol-12-myristate-13-acetate (10 µM) blocked SP-induced I{kappa}B{alpha} and p65 phosphorylation and IL-8 production. The PKC{delta} inhibitor rottlerin at a low concentration (1 µM), but not pseudosubstrate PKC{theta} and PKC{epsilon} inhibitors (10 µM), significantly reduced IL-8 secretion. PKC{delta} silencing by RNA interference reduced PKC{delta} protein expression and SP-induced PKC{delta} phosphorylation that was associated with diminished IL-8 promoter and NF-{kappa}B luciferase activities in response to SP. Moreover, overexpression of wild-type PKC{delta} increased SP-induced IL-8 promoter- and NF-{kappa}B-driven luciferase activities that were rottlerin-sensitive. We conclude that PKC{delta} plays an important role in SP-induced proinflammatory signaling in human colonocytes.

Received April 13, 2005; accepted May 23, 2005.

Address correspondence to: Dr. Charalabos Pothoulakis, Beth Israel Deaconess Medical Center, Division of Gastroenterology, Dana 501, 330 Brookline Avenue, Boston, MA 02215. E-mail: cpothoul{at}bidmc.harvard.edu




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