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

Protein kinase D2 mediates lysophosphatidic acid-induced interleukin 8 production in... The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD 2 activation and the potential contribution of PKD 2 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 PKD 2 , as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD 2 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 PKD 2 activity. LPA induced a striking increase in IL-8 production and stimulated NF-κB activation, as measured by NF-κB-DNA binding, NF-κB-driven luciferase reporter activity, and IκBα phosphorylation. PKD 2 gene silencing utilizing small interfering RNAs targeting distinct PKD 2 sequences dramatically reduced LPA-stimulated NF-κB promoter activity and IL-8 production. PKD 2 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-κB-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 Address for reprint requests and other correspondence: E. Rozengurt, 900 Veteran Ave., Warren Hall, Rm. 11–144, Dept. of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1786 (e-mail: erozengurt@mednet.ucla.edu ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Cell Physiology The American Physiological Society

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

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References (68)

Publisher
The American Physiological Society
Copyright
Copyright © 2010 the American Physiological Society
ISSN
0363-6143
eISSN
1522-1563
DOI
10.1152/ajpcell.00308.2006
pmid
16928771
Publisher site
See Article on Publisher Site

Abstract

The signaling pathways mediating lysophosphatidic acid (LPA)-stimulated PKD 2 activation and the potential contribution of PKD 2 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 PKD 2 , as measured by in vitro kinase assay and phosphorylation at the activation loop (Ser706/710) and autophosphorylation site (Ser876). PKD 2 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 PKD 2 activity. LPA induced a striking increase in IL-8 production and stimulated NF-κB activation, as measured by NF-κB-DNA binding, NF-κB-driven luciferase reporter activity, and IκBα phosphorylation. PKD 2 gene silencing utilizing small interfering RNAs targeting distinct PKD 2 sequences dramatically reduced LPA-stimulated NF-κB promoter activity and IL-8 production. PKD 2 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-κB-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 Address for reprint requests and other correspondence: E. Rozengurt, 900 Veteran Ave., Warren Hall, Rm. 11–144, Dept. of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1786 (e-mail: erozengurt@mednet.ucla.edu )

Journal

AJP - Cell PhysiologyThe American Physiological Society

Published: Feb 1, 2007

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