RhoA-mediated signaling up-regulates hepatocyte growth factor gene and protein expression in response to apoptotic cells
RhoA-mediated signaling up-regulates hepatocyte growth factor gene and protein expression in response to apoptotic cells
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DOI：
10.1189/jlb.0710414
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发表时间：
2011-03-01
影响因子：
5.5
通讯作者：
Kang, Jihee Lee
中科院分区：
文献类型：
--
作者：
Park, Hyun-Jung;Choi, Youn-Hee;Kang, Jihee Lee
巨噬细胞清除凋亡细胞可诱导HGF的分泌。我们研究了巨噬细胞暴露于凋亡细胞时HGF mRNA和蛋白表达的调节机制。RAW 264.7巨噬细胞与凋亡的Jurkat细胞相互作用，但不与活细胞相互作用，导致HGF mRNA和蛋白的表达。RAW 264.7细胞暴露于凋亡细胞可诱导RhoA、PI3K/Akt通路和包括p38MAPK、ERK和JNK在内的MAPK的激活。药物抑制剂或RhoA特异性siRNA下调RhoA/Rho激酶通路，可通过Akt和MAPKs的磷酸化抑制巨噬细胞HGF mRNA和蛋白的表达。抑制PI3K使Akt和MAPKs的磷酸化水平降低。抑制JNK，但不抑制p38MAPK和ERK，可降低Akt的磷酸化。药物抑制剂PI3K和MAPKs可阻断HGF基因和蛋白的表达。其他类型的凋亡细胞，如HeLa细胞和小鼠胸腺细胞，也可以通过RhoA依赖的途径诱导HGF mRNA。可能，RhoA依赖的信号通路是在原代细胞中诱导HGF mRNA以响应凋亡细胞所必需的。HGFR阻断抗体不改变细胞诱导的RhoA、Akt和MAPKs的激活以及HGF的产生。总体而言，这些数据提供了证据，即RhoA/Rho激酶通路的激活上调了HGF转录产物的产生，以应对细胞凋亡。J.Leukoc。比奥尔。：399411；2011年。
Clearance of apoptotic cells by macrophages induces HGF secretion. We examined the regulatory mechanisms of HGF mRNA and protein expression in macrophages upon exposure to apoptotic cells. The interaction of RAW 264.7 macrophages with apoptotic Jurkat cells, but not with viable cells, resulted in expression of HGF mRNA and protein. Exposure of RAW 264.7 cells to apoptotic cells induced activation of RhoA, the PI3K/Akt pathway, and MAPKs, including p38 MAPK, ERK, and JNK. Down-regulation of the RhoA/Rho kinase pathway by pharmacological inhibitors or a RhoA-specific siRNA suppressed HGF mRNA and protein expression by macrophages in response to apoptotic cells through the phosphorylation of Akt and the MAPKs. Inhibition of PI3K decreased phosphorylation of Akt and the MAPKs. Inhibition of JNK, but not p38 MAPK and ERK, reduced Akt phosphorylation. The pharmacological inhibitor of PI3K and the MAPKs blocked HGF mRNA and protein expression. Other types of apoptotic cells, such as HeLa cells and murine thymocytes, could also induce HGF mRNA through the RhoA-dependent pathway. Likely, the RhoA-dependent signaling pathway was required for HGF mRNA induction in primary cells of peritoneal macrophages in response to apoptotic cells. An HGFR-blocking antibody did not alter apoptotic cell-induced activation of RhoA, Akt, and the MAPKs, as well as HGF production. Overall, the data provide evidence that activation of the RhoA/Rho kinase pathway up-regulates transcriptional HGF production in response to apoptotic cells. J. Leukoc. Biol. 89: 399-411; 2011.