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

Journal Article · Fri Sep 08 00:00:00 EDT 2006 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2006.07.015· OSTI ID:20854452

Patel, Devang N ^[1]; Bailey, Steven R ^[1]; Gresham, John K ^[1]; Schuchman, David B ^[1]; Shelhamer, James H ^[2]; Goldstein, Barry J ^[3]; Foxwell, Brian M ^[4]; Stemerman, Michael B ^[5]; Maranchie, Jodi K ^[6]; Valente, Anthony J ^[1]; Mummidi, Srinivas ^[1]; Chandrasekar, Bysani ^[7]

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1. Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, TX (United States)
2. Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD (United States)
3. Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA (United States)
4. Imperial College of Science, Technology and Medicine, London (United Kingdom)
5. Division of Biomedical Sciences, University of California at Riverside, Riverside, CA (United States)
6. Department of Surgery, University of Massachusetts, Worcester, MA (United States)
7. Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, TX (United States) and Department of Veterans Affairs South Texas Veterans Health Care System, San Antonio, TX (United States)

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-{kappa}B (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.

• OSTI ID: 20854452
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 347, Issue 4; Other Information: DOI: 10.1016/j.bbrc.2006.07.015; PII: S0006-291X(06)01554-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
ARTERIOSCLEROSIS
CELL PROLIFERATION
CHLORIDES
CORONARIES
ENDOTOXINS
INHIBITION
MUSCLES
OXIDASES
PATHOGENESIS