Expression of a functional c5a receptor in regenerating hepatocytes and its involvement in a proliferative signaling pathway in rat
Expression of a functional c5a receptor in regenerating hepatocytes and its involvement in a proliferative signaling pathway in rat
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DOI：
10.4049/jimmunol.173.5.3418
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发表时间：
2004-09-01
影响因子：
4.4
通讯作者：
Fontaine, M
中科院分区：
文献类型：
--
作者：
Daveau, M;Benard, M;Fontaine, M
补体系统的激活产生过敏毒素C5 a，其活性通过其与广泛表达的C5 aR结合来介导。已知C5 aR mRNA和蛋白质表达在炎症条件下在大鼠肝细胞中被诱导。然而，很少有人知道的C5 a/C5 aR复合物在肝脏中的作用和它的参与在增殖过程中。我们已经评估了C5 aR的表达在再生大鼠肝细胞部分肝切除术后，在肝细胞培养。在再生肝的肝细胞中以及在培养诱导的应激下的正常肝细胞中观察到C5 aR诱导。还评价了C5 a激动剂刺激对生长因子/受体对（肝细胞生长因子/c-Met）合成的影响。我们的数据表明肝细胞生长因子和c-Met mRNA的表达上调，但我们未能观察到C5 a在培养中的直接促有丝分裂作用。然而，一个显着增加细胞周期蛋白E和D1 mRNA水平的表达，以及增加BrdU掺入，观察到大鼠静脉注射C5 a激动剂注射后，80%的部分肝切除术。这些研究首次证明：1）C5 aR在肝再生过程中上调，2）C5 a与C5 aR的结合促进生长反应，3）C5 aR参与细胞周期信号通路。总之，这些发现指出了一个新的作用，肝脏C5 aR牵连这种补体系统的正常或异常增殖途径的背景下。
Activation of the complement system generates the anaphylatoxin C5a whose activities are mediated through its binding to the widely expressed C5aR. C5aR mRNA and protein expressions are known to be induced in rat hepatocytes under inflammatory conditions. However, little is known about the role of the C5a/C5aR complex in liver and its involvement during a proliferative process. We have evaluated the expression of C5aR in regenerating rat hepatocytes following a partial hepatectomy and in hepatocyte cultures. C5aR induction was observed in hepatocytes from regenerating liver, as well as in normal hepatocytes under a culture-induced stress. The effect of a stimulation by a C5a agonist upon the synthesis of a growth factor/receptor pair (hepatocyte growth factor/c-Met) was also evaluated. Our data demonstrated an up-regulated expression of hepatocyte growth factor and c-Met mRNAs, but we failed to observe a direct mitogenic effect of C5a in culture. However, a significantly increased expression of cyclin E and D1mRNA levels, as well as an increased BrdU incorporation, were observed in rats given an i.v. C5a agonist injection following an 80% partial hepatectomy. These studies demonstrate for the first time that: 1) C5aR is up-regulated during liver regeneration, 2) the binding of C5a to C5aR promotes a growth response, and 3) C5aR is involved in a cell cycle signaling pathway. Taken together, these findings point to a novel role for the hepatic C5aR implicating this complement system in the context of normal or abnormal proliferative pathways.