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  • Title: Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves protein kinase Cdelta activation.
    Author: Koon HW, Zhao D, Zhan Y, Simeonidis S, Moyer MP, Pothoulakis C.
    Journal: J Pharmacol Exp Ther; 2005 Sep; 314(3):1393-400. PubMed ID: 15917399.
    Abstract:
    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-kappaB)-driven proinflammatory cytokines from colonic epithelial cells. However, the signal transduction pathways by which SP-NK-1R interaction induces NF-kappaB 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 PKCdelta, PKC, and PKCepsilon, followed by I-kappaB kinase, IkappaBalpha, and p65 phosphorylation. Depletion of PKC by phorbol-12-myristate-13-acetate (10 microM) blocked SP-induced IkappaBalpha and p65 phosphorylation and IL-8 production. The PKCdelta inhibitor rottlerin at a low concentration (1 microM), but not pseudosubstrate PKC and PKCepsilon inhibitors (10 microM), significantly reduced IL-8 secretion. PKCdelta silencing by RNA interference reduced PKCdelta protein expression and SP-induced PKCdelta phosphorylation that was associated with diminished IL-8 promoter and NF-kappaB luciferase activities in response to SP. Moreover, overexpression of wild-type PKCdelta increased SP-induced IL-8 promoter- and NF-kappaB-driven luciferase activities that were rottlerin-sensitive. We conclude that PKCdelta plays an important role in SP-induced proinflammatory signaling in human colonocytes.
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