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
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
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DOI：
10.1074/jbc.m311660200
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发表时间：
2004-01-30
影响因子：
4.8
通讯作者：
Mummidi, S
中科院分区：
文献类型：
--
作者：
Chandrasekar, B;Bysani, S;Mummidi, S
CXCL 16是近年来发现的一种跨膜趋化因子，在人主动脉平滑肌细胞（ASMC）中表达。它促进巨噬细胞摄取低密度脂蛋白，导致泡沫细胞形成。然而，目前尚不清楚ASMC是否表达CXCR 6，CXCL 16的受体，或CXCL 16是否影响ASMC生物学。为了剖析CXCL 16引起的生物学和信号转导途径，在加入CXCL 16之前，用药理学抑制剂处理人主动脉平滑肌细胞（HASMC）或用途径特异性显性阴性或激酶死亡表达载体瞬时转染。HASMC在基础条件下表达CXCR 6。HASMC暴露于CXCL 16增加NF-κ B DNA结合活性，诱导κ B驱动的荧光素酶活性，并以NF-κ B依赖性方式上调肿瘤坏死因子α表达。然而，用百日咳毒素（G（i）抑制剂）、渥曼青霉素或LY 294002（磷脂酰肌醇3-激酶（PI 3 K抑制剂））或Akt抑制剂或显性阴性（dn）PI 3 K γ、dnPDK-1、激酶死亡（kd）Akt、kdIKK-β、dnIKK-γ、dnIkappaB-α或dnIkappaB-β的过表达治疗显著减弱CXCL 16诱导的NF-κ B活化。此外，CXCL 16以NF-κ B依赖性方式增加细胞-细胞粘附并诱导细胞增殖。总之，CXCL 16是NF-κ B的有效和直接激活剂，并诱导κ B依赖性促炎基因转录。CXCL 16介导的NF-κ B活化通过异源三聚体G蛋白、PI 3 K、PDK-1、Akt和IkappaB激酶（IKK）发生。CXCL 16诱导IkappaB磷酸化和降解。最重要的是，CXCL 16增加细胞-细胞粘附并诱导kappaB依赖的ASMC增殖，表明CXCL 16可能在动脉粥样硬化血管疾病的发生和进展中起重要作用。
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.