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.
Copyright © 2012 S. Karger AG, Basel.
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology
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Cells, Cultured / drug effects
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Cells, Cultured / enzymology
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Cells, Cultured / physiology
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Collagen
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Culture Media, Serum-Free / pharmacology
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Endothelial Cells / drug effects*
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Endothelial Cells / enzymology
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Endothelial Cells / physiology
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Endothelium, Vascular / cytology*
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Enzyme Activation / drug effects
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Gels
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Humans
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In Vitro Techniques
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / physiology*
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Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 14 / physiology*
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / physiology*
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Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 8 / physiology*
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Protein Kinase Inhibitors / pharmacology
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Pulmonary Artery / cytology*
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RNA Interference
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RNA, Small Interfering / pharmacology
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Recombinant Proteins / pharmacology
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Tumor Necrosis Factor-alpha / pharmacology*
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Tumor Necrosis Factor-alpha / physiology
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Vasculitis / enzymology
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Vasculitis / physiopathology
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Wound Healing / drug effects
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Wound Healing / physiology*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / physiology*
Substances
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Culture Media, Serum-Free
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Gels
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Collagen
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 14
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases