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Received for publication April 14, 2005.
Revised May 20, 2005.
Accepted for publication May 23, 2005.
activation
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-
B)-driven proinflammatory cytokines from colonic epithelial cells. However, the signal transduction pathways by which SP-NK-1R interaction induces nuclear factor kappa B (NF-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 non-transformed 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
, PKC
, and PKC
, followed by I-B kinase (IKK), IB
and p65 phosphorylation. Depletion of PKC by phorbol-12-myristate-13-acetate (PMA) (10 µM) blocked SP-induced IB and p65 phosphorylation and IL-8 production. The PKC inhibitor rottlerin, at a low concentration (1 µM), but not pseudosubstrate PKC, and PKC inhibitors (10 µM) significantly reduced IL-8 secretion. PKC silencing by RNA interference reduced PKC protein expression and SP-induced PKC phosphorylation that was associated with diminished IL-8 promoter and NF-B luciferase activities in response to SP. Moreover, over-expression of wild-type PKC increased SP induced IL-8 promoter- and NF-B-driven luciferase activities that were rottlerin-sensitive. We conclude that PKC plays an important role in SP-induced proinflammatory signaling in human colonocytes.
Key words:
Protein kinase, epithelial, gastrointestinal system, inflammation, interleukin-8, signal transduction
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