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RECEPTORS AND SIGNAL TRANSDUCTION

Protein kinase D₂ mediates lysophosphatidic acid-induced interleukin 8 production in nontransformed human colonic epithelial cells through NF-B

¹Department of Medicine, School of Medicine, CURE: Digestive Diseases Research Center and Molecular Biology Institute, University of California, Los Angeles, California; and ²INCELL Corporation, San Antonio, Texas

Submitted 2 June 2006 ; accepted in final form 16 August 2006

The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD₂ activation and the potential contribution of PKD₂ in regulating LPA-induced interleukin 8 (IL-8) secretion in nontransformed, human colonic epithelial NCM460 cells were examined. Treatment of serum-deprived NCM460 cells with LPA led to a rapid and striking activation of PKD₂, as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD₂ activation induced by LPA was abrogated by preincubation with selective PKC inhibitors GF-I and Ro-31-8220 in a dose-dependent manner. These inhibitors did not have any direct inhibitory effect on PKD₂ activity. LPA induced a striking increase in IL-8 production and stimulated NF-B activation, as measured by NF-B-DNA binding, NF-B-driven luciferase reporter activity, and IB phosphorylation. PKD₂ gene silencing utilizing small interfering RNAs targeting distinct PKD₂ sequences dramatically reduced LPA-stimulated NF-B promoter activity and IL-8 production. PKD₂ activation is a novel early event in the biological action of LPA and mediates LPA-stimulated IL-8 secretion in NCM460 cells through a NF-B-dependent pathway. Our results demonstrate, for the first time, the involvement of a member of the PKD family in the production of IL-8, a potent proinflammatory chemokine, by epithelial cells.

NCM460 cells; protein kinase C; CXCL8; phorbol esters

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