Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation.
Hepatic stellate cells express functional CXCR4: role in stromal cell-derived factor-1alpha-mediated stellate cell activation.
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DOI：
10.1002/hep.22890
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发表时间：
2009-06
期刊：
影响因子：
13.5
通讯作者：
Bansal, Meena B.
中科院分区：
文献类型：
--
作者：
Hong, Feng;Tuyama, Ana;Lee, Ting Fang;Loke, Johnny;Agarwal, Ritu;Cheng, Xin;Garg, Anita;Fiel, M. Isabel;Schwartz, Myron;Walewski, Jose;Branch, Andrea;Schecter, Alison D.;Bansal, Meena B.
趋化因子与其受体的相互作用与肝星状细胞(HSC)的激活有关。CXCR4信使核糖核酸在丙型肝炎肝硬变患者肝脏中的表达增加，其内源性配体基质细胞衍生因子-1α(SDF-1α)的水平与这些患者肝纤维化程度的增加有关。CXCR4在HSCs中的表达尚未见报道。因此，我们检测了肝星状细胞在体内和体外是否表达CXCR4，并探讨了SDF-1α/CXCR4受体参与是否促进了肝星状细胞的激活、纤维化形成和增殖。CXCR4和SDF1α在丙型肝炎肝硬变肝组织中表达增加，免疫荧光和免疫组织化学染色证实HSC体内表达CXCR4。永生化的人类星状细胞和原代人类HSCs都表达CXCR4，细胞表面受体的表达随着培养的进展而增加。用重组SDF-1α处理星状细胞可增加α-平滑肌肌动蛋白和I型胶原的表达，并刺激HSC增殖，且呈剂量依赖关系。抑制剂研究表明，依赖于α/CXCR4的胞外信号调节激酶1/2和AKT磷酸化介导了I型胶原表达和星状细胞增殖的影响。HSCs在体内和体外均表达CXCR4受体。SDF-1α激活CXCR4受体是通过影响肝星状细胞的活化、纤维化形成和增殖而致纤维化的。细胞外信号调节激酶1/2和磷脂酰肌醇3-激酶通路介导SDF-1α诱导的肝星状细胞I型胶原表达和增殖。CXCR4小分子抑制剂的出现使该受体成为抗纤维化治疗的靶点。
Chemokine interactions with their receptors have been implicated in hepatic stellate cell (HSC) activation. The hepatic expression of CXCR4 messenger RNA is increased in hepatitis C cirrhotic livers and plasma levels of its endogenous ligand, stromal cell–derived factor-1α (SDF-1α), correlate with increased fibrosis in these patients. The expression of CXCR4 by HSCs has not been reported. We therefore examined whether HSCs express CXCR4 in vivo and in vitro and explored whether SDF-1α/CXCR4 receptor engagement promotes HSC activation, fibrogenesis, and proliferation. The hepatic protein expression of both CXCR4 and SDF-1α is increased in hepatitis C cirrhotic livers and immunoflourescent and immunohistochemical staining confirms that HSCs express CXCR4 in vivo. Immortalized human stellate cells as well as primary human HSCs express CXCR4, and cell surface receptor expression increases with progressive culture-induced activation. Treatment of stellate cells with recombinant SDF-1α increases expression of α-smooth muscle actin and collagen I and stimulates a dose-dependent increase in HSC proliferation. Inhibitor studies suggest that SDF-1α/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediate effects on collagen I expression and stellate cell proliferation. HSCs express CXCR4 receptor in vivo and in vitro. CXCR4 receptor activation by SDF-1α is profibrogenic through its effects on HSC activation, fibrogenesis, and proliferation. Extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase pathways mediate SDF-1α–induced effects on HSC expression of collagen I and proliferation. The availability of small molecule inhibitors of CXCR4 make this receptor an appealing target for antifibrotic approaches.
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影响因子：
24.5
作者：
Xu, L;Hui, AY;Eng, FJ
通讯作者：
Eng, FJ
DOI：
10.1073/pnas.0604728103
发表时间：
2006-10-17
影响因子：
11.1
作者：
Xiang, Jinhua;McLinden, James H.;Stapleton, Jack T.
通讯作者：
Stapleton, Jack T.
影响因子：
20.1
作者：
Abi-Younes, S;Sauty, A;Luster, AD
通讯作者：
Luster, AD
影响因子：
13.5
作者：
Schrage, Arnhild;Wechsung, Katja;Klugewitz, Katja
通讯作者：
Klugewitz, Katja
影响因子：
6
作者：
Shackel, NA;McGuinness, PH;McCaughan, GW
通讯作者：
McCaughan, GW