title: 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 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.
authors.affiliation: Division of Endocrinology and Metabolism, Kagawa University, Kagawa, USA.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kanaji
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.forename: Xingqi
authors.initials: X
authors.lastname: Wang
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sato
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Gunji
authors.forename: Hesham
authors.initials: H
authors.lastname: Basma
authors.forename: Joel
authors.initials: J
authors.lastname: Michalski
authors.forename: Maha
authors.initials: M
authors.lastname: Farid
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D003094:Collagen; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology*; D004789:Enzyme Activation / Q000187:drug effects; D005782:Gels; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000502:physiology; D014657:Vasculitis / Q000201:enzymology / Q000503:physiopathology; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D016895:Culture Media, Serum-Free; D005782:Gels; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases