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.

Tumor necrosis factor (TNF)-alpha can alter tissue repair functions in a variety of cells including endothelial cells. However, the mechanism by which TNF-alpha 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-alpha on the tissue repair functions of human pulmonary artery endothelial cells (HPAECs). TNF-alpha protected HPAECs from undergoing apoptosis induced by serum and growth factor deprivation, augmented collagen gel contraction, and stimulated wound closure. TNF-alpha activated c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38. Inhibitors of JNK (SP600125, 5 mu M) or ERK1/2 (PD98059, 5 mu M) significantly inhibited TNF-alpha-stimulated cell survival, contraction of collagen gels, and wound closure. In contrast, the p38 inhibitor SB203580 (5 mu M) further amplified all of the TNF-alpha effects on HPAECs. TNF-alpha specifically activated p38 alpha but not other p38 isoforms and suppression of p38 alpha by an siRNA resulted in further amplification of the TNF-alpha effect. These results suggest that TNF-alpha stimulates tissue repair functions of HPAECs, and this may be mediated, at least in part, positively via JNK and ERK1/2, and negatively through p38 alpha. MAPKs may play a role in endothelial cell-mediated tissue repair, especially in an inflammatory milieu where TNF-alpha is present. Copyright (c) 2012 S. Karger AG, Basel