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

J Vasc Res. 2013;50(2):145-56. doi: 10.1159/000345525. Epub 2012 Dec 18.

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 µM) or ERK1/2 (PD98059, 5 µM) significantly inhibited TNF-α-stimulated cell survival, contraction of collagen gels, and wound closure. In contrast, the p38 inhibitor SB203580 (5 µM) 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.

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cells, Cultured / drug effects
  • Cells, Cultured / enzymology
  • Cells, Cultured / physiology
  • Collagen
  • Culture Media, Serum-Free / pharmacology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / enzymology
  • Endothelial Cells / physiology
  • Endothelium, Vascular / cytology*
  • Enzyme Activation / drug effects
  • Gels
  • Humans
  • In Vitro Techniques
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / physiology*
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 14 / physiology*
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / physiology*
  • Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 8 / physiology*
  • Protein Kinase Inhibitors / pharmacology
  • Pulmonary Artery / cytology*
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Recombinant Proteins / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Tumor Necrosis Factor-alpha / physiology
  • Vasculitis / enzymology
  • Vasculitis / physiopathology
  • Wound Healing / drug effects
  • Wound Healing / physiology*
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / physiology*

Substances

  • Culture Media, Serum-Free
  • Gels
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Collagen
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 14
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 8
  • p38 Mitogen-Activated Protein Kinases