TLR4-NOX4-AP-1 signaling mediates lipopolysaccharide-induced CXCR6 expression in human aortic smooth muscle cells

Devang N. Patel, Steven R. Bailey, John K. Gresham, David B. Schuchman, James H. Shelhamer, Barry J. Goldstein, Brian M. Foxwell, Michael B. Stemerman, Jodi K. Maranchie, Anthony J. Valente, Srinivas Mummidi, Bysani Chandrasekar

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

CXCL16 is a transmembrane non-ELR CXC chemokine that signals via CXCR6 to induce aortic smooth muscle cell (ASMC) proliferation. While bacterial lipopolysaccharide (LPS) has been shown to stimulate CXCL16 expression in SMC, its effects on CXCR6 are not known. Here, we demonstrate that LPS upregulates CXCR6 mRNA, protein, and surface expression in human ASMC. Inhibition of TLR4 with neutralizing antibodies or specific siRNA interference blocked LPS-mediated CXCR6 expression. LPS stimulated both AP-1 (c-Fos, c-Jun) and NF-κB (p50 and p65) activation, but only inhibition of AP-1 attenuated LPS-induced CXCR6 expression. Using dominant negative expression vectors and siRNA interference, we demonstrate that LPS induces AP-1 activation via MyD88, TRAF6, ERK1/2, and JNK signaling pathways. Furthermore, the flavoprotein inhibitor diphenyleniodonium chloride significantly attenuated LPS-mediated AP-1-dependent CXCR6 expression, as did inhibition of NOX4 NADPH oxidase by siRNA. Finally, CXCR6 knockdown inhibited CXCL16-induced ASMC proliferation. These results demonstrate that LPS-TLR4-NOX4-AP-1 signaling can induce CXCR6 expression in ASMC, and suggest that the CXCL16-CXCR6 axis may be an important proinflammatory pathway in the pathogenesis of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)1113-1120
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume347
Issue number4
DOIs
StatePublished - Sep 8 2006

Keywords

  • Atherosclerosis
  • Coronary disease
  • Endotoxins
  • MAP kinase
  • Signal transduction

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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