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

Abstract

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.

Apoptotic cell clearance and fibrotic lung disease

“…Their results show that instillation of apoptotic cells into the lungs leads to an immediate increase in HGF gene expression and protein levels in the lungs. These findings are in line with previous work that shows that efferocytosis induces HGF production by macrophages [5, 7]. Accordingly, there is strong evidence suggesting that HGF upregulates antiapoptotic signalling pathways in epithelial and endothelial cells, rendering them less susceptible to oxidant and Fas-mediated apoptosis [8], both of which have been implicated in bleomycin-induced lung injury.…”

RhoA/Phosphatidylinositol 3-Kinase/Protein Kinase B/Mitogen-Activated Protein Kinase Signaling after Growth Arrest–Specific Protein 6/Mer Receptor Tyrosine Kinase Engagement Promotes Epithelial Cell Growth and Wound Repair via Upregulation of Hepatocyte Growth Factor in Macrophages

“…Akt and JNK signaling appear to cross-talk on Gas6 stimulation. Collectively, these findings suggest that Gas6 induces mRNA expression and production of HGF through activation of RhoA/Rho kinase/PI3K/Akt/MAP kinases, including p38 MAP kinase, ERK and JNK, similar to apoptotic cell stimulation (Park et al, 2011).…”

“…Consequently, macrophages turn off production of proinflammatory cytokines and lipid mediators and launch an antiinflammatory transcriptional program characterized by release of transforming growth factor-b (TGF-b), interleukin-10, and prostaglandin E 2 (Fadok et al, 1998). Furthermore, our previous studies indicate that apoptotic cells and Gas6 are capable of triggering hepatocyte growth factor (HGF) production by macrophages (Park et al, 2011(Park et al, , 2012. Moreover, apoptotic cells bind the Mer receptor to induce HGF mRNA and protein expression in macrophages via a RhoA-dependent pathway (Park et al, 2012).…”

Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes

“…M⌽ efferocytosis of apoptotic cells may be involved. NPD1 enhances the M⌽ phagocytosis capability (60,62), and the M⌽ engulfment of apoptotic cells leads to the production of HGF with concomitant activation of PI3K, MAPK, and Rho A pathways (54,55). M⌽ efferocytosis also induces microRNA-21 by silencing PTEN and GSK3␤, triggers release of IL-10, and suppresses LPS-induced TNF-␣ expression (17).…”