期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 292, 期 2, 页码 C767-C777出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00308.2006
关键词
NCM460 cells; protein kinase C; CXCL8; phorbol esters
资金
- NIDDK NIH HHS [K08 DK-063983, R0-1 DK-56930, R0-1 DK-55003] Funding Source: Medline
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-kappa B activation, as measured by NF-kappa B- DNA binding, NF-kappa B-driven luciferase reporter activity, and I kappa B alpha phosphorylation. PKD2 gene silencing utilizing small interfering RNAs targeting distinct PKD2 sequences dramatically reduced LPA-stimulated NF-kappa 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-kappa 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.
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