期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 279, 期 5, 页码 3188-3196出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M311660200
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资金
- NHLBI NIH HHS [HL68020] Funding Source: Medline
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-kappaB DNA binding activity, induced kappaB-driven luciferase activity, and up-regulated tumor necrosis factor-alpha expression in an NF-kappaB-dependent manner. However, treatment with pertussis toxin (G(i) inhibitor), wortmannin or LY294002 (phosphatidylinositol 3-kinase (PI3K inhibitors)), or Akt inhibitor or overexpression of dominant-negative (dn) PI3Kgamma, dnPDK-1, kinase-dead (kd) Akt, kdIKK-beta, dnIKK-gamma, dnIkappaB-alpha, or dnIkappaB-beta significantly attenuated CXCL16-induced NF-kappaB activation. Furthermore, CXCL16 increased cell-cell adhesion and induced cellular proliferation in an NF-kappaB-dependent manner. In conclusion, CXCL16 is a potent and direct activator of NF-kappaB and induces kappaB-dependent proinflammatory gene transcription. CXCL16-mediated NF-kappaB activation occurred via heterotrimeric G proteins, PI3K, PDK-1, Akt, and IkappaB kinase (IKK). CXCL16 induced IkappaB phosphorylation and degradation. Most importantly, CXCL16 increased cell-cell adhesion and induced kappaB-dependent ASMC proliferation, indicating that CXCL16 may play an important role in the development and progression of atherosclerotic vascular disease.
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