CXCL16 Signals via Gi, Phosphatidylinositol 3-Kinase, Akt, IκB Kinase, and Nuclear Factor-κB and Induces Cell-Cell Adhesion and Aortic Smooth Muscle Cell Proliferation

Bysani Chandrasekar, Sailaja Bysani, Srinivas Mummidi

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

CXCL16, a recently discovered transmembrane chemokine, is expressed in human aortic smooth muscle cell (ASMC). It facilitates uptake of low density lipoproteins by macrophages, resulting in foam cell formation. However, it is not known whether ASMC express CXCR6, the receptor for CXCL16, or whether CXCL16 affects ASMC biology. To dissect the biological and signal transduction pathways elicited by CXCL16, human aortic smooth muscle cells (HASMC) were treated with pharmacological inhibitors or transiently transfected with pathway-specific dominant-negative or kinase-dead expression vectors prior to the addition of CXCL16. HASMC expressed CXCR6 at basal conditions. Exposure of HASMC to CXCL16 increased NF-κB DNA binding activity, induced κB-driven luciferase activity, and up-regulated tumor necrosis factor-α expression in an NF-κB-dependent manner. However, treatment with pertussis toxin (Gi inhibitor), wortmannin or LY294002 (phosphatidylinositol 3-kinase (PI3K inhibitors)), or Akt inhibitor or overexpression of dominant-negative (dn) PI3Kγ, dnPDK-1, kinase-dead (kd) Akt, kdIKK-β, dnIKK-γ, dnIKB-α, or dnIKB-β significantly attenuated CXCL16-induced NF-κB activation. Furthermore, CXCL16 increased cell-cell adhesion and induced cellular proliferation in an NF-κ B-dependent manner. In conclusion, CXCL16 is a potent and direct activator of NF-κB and induces βB-dependent proinflammatory gene transcription. CXCL16-mediated NF-κB activation occurred via heterotrimeric G proteins, PI3K, PDK-1, Akt, and IκB kinase (IKK). CXCL16 induced IκB phosphorylation and degradation. Most importantly, CXCL16 increased cell-cell adhesion and induced κB-dependent ASMC proliferation, indicating that CXCL16 may play an important role in the development and progression of atherosclerotic vascular disease.

Original languageEnglish (US)
Pages (from-to)3188-3196
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number5
DOIs
StatePublished - Jan 30 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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