Differential Roles of JNK, ERK1/2, and p38 Mitogen-Activated Protein Kinases on Endothelial Cell Tissue Repair Functions in Response to Tumor Necrosis Factor-α

Abstract

Tumor necrosis factor (TNF)-α can alter tissue repair functions in a variety of cells including endothelial cells. However, the mechanism by which TNF-α mediates these functional changes has not fully been studied. We investigated the role of mitogen-activated protein kinases (MAPKs) on mediating the regulatory effect of TNF-α on the tissue repair functions of human pulmonary artery endothelial cells (HPAECs). TNF-α protected HPAECs from undergoing apoptosis induced by serum and growth factor deprivation, augmented collagen gel contraction, and stimulated wound closure. TNF-α activated c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38. Inhibitors of JNK (SP600125, 5 µ<smlcap>m</smlcap>) or ERK1/2 (PD98059, 5 µ<smlcap>m</smlcap>) significantly inhibited TNF-α-stimulated cell survival, contraction of collagen gels, and wound closure. In contrast, the p38 inhibitor SB203580 (5 µ<smlcap>m</smlcap>) further amplified all of the TNF-α effects on HPAECs. TNF-α specifically activated p38α but not other p38 isoforms and suppression of p38α by an siRNA resulted in further amplification of the TNF-α effect. These results suggest that TNF-α stimulates tissue repair functions of HPAECs, and this may be mediated, at least in part, positively via JNK and ERK1/2, and negatively through p38α. MAPKs may play a role in endothelial cell-mediated tissue repair, especially in an inflammatory milieu where TNF-α is present.

A Novel Small-Molecule Integrin Antagonist Inhibits Cells Adhesion Followed By Anoikis in Endothelial Cells - A Comparative Analysis with Cilengitide

“…Experimental data obtained from transmembrane migration assays revealed that AV-38/398 suppresses migration of endothelial cells in a dose-dependent manner. Western blotting experiments clearly showed a decrease in the activation state integrin-linked signaling pathways involved in cell migration and proliferation, such as FAK, Akt, and ERK1/2 [30,34]. Our results partially overlap with those reported for cilengitide in HUVECs [14].…”

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

“…26 We show that in TNFα-stimulated ECs, 6-MP decreases the amount of JNK phosphorylation (p-JNK) and thus reduces JNK activation ( Figure 3A and 3B). A similar reduction in p-JNK was also observed when a Rac1 inhibitor was used, suggesting that indeed inactivation of Rac1 by 6-MP could be responsible for reduced levels of p-JNK.…”

Probucol Protects Against Asymmetric Dimethylarginine-Induced Apoptosis in the Cultured Human Brain Microvascular Endothelial Cells

“…A wide variety of stimuli such as oxidative stress can induce apoptosis of endothelial cells and endothelial dysfunction, which may be regulated by different signal pathways (Maruyama et al 2012;Qin et al 2015). Mitogen-activated protein kinases (MAPKs), including extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK), and p38, are a family of central signaling molecules that respond to numerous stimuli and are known to participate in cell survival and death decisions (Hardie 2011;Kanaji et al 2013). Moreover, the activation of JNK and p38 MAPK phosphorylation can induce apoptotic responses in endothelial cells (Yoshizuka et al 2012).…”