RhoA-mediated signaling up-regulates hepatocyte growth factor gene and protein expression in response to apoptotic cells

Journal of Leukocyte Biology

Youn-Hee Choi¹  Young Joo Cho²  Hyun-Jung Park¹  Peter M. Henson and³  Jihee Lee Kang¹ 

[1] Departments of Physiology and  Internal Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Korea; Internal Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Korea;Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA  Internal Medicine, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Korea;

关键词: macrophage;    PI3K/Akt;    MAPK;   

DOI  :  10.1189/jlb.0710414

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown