title: Post-transcriptional regulation of TNF-induced expression of ICAM-1 and IL-8 in human lung microvascular endothelial cells: an obligatory role for the p38 MAPK-MK2 pathway dissociated with HSP27.
abstract: The tumor necrosis factor-alpha (TNF)-induced inflammatory response in human lung microvascular endothelial cells (MVECs) is an early event in acute lung injury. Studies have shown that p38 mitogen-activated protein kinase (MAPK), MAPK-activated protein kinase 2 (MK2) and heat shock protein 27 (HSP27) are involved in the expression of pro-inflammatory mediators in other cell types. However, their role in the TNF-induced inflammatory response in lung MVECs has not been determined. We evaluated the role of p38 MAPK, MK2 and HSP27 in regulating the TNF-induced expression of ICAM-1 and IL-8 in human lung MVECs. Inhibition of p38 MAPK reduced ICAM-1 and IL-8 expression without influencing NF-kappaB activation or ICAM-1 and IL-8 mRNA levels. TNF stimulation induced p38 MAPK-dependent phosphorylation of MK2 and HSP27. MK2 silencing reduced ICAM-1 and IL-8 expression without influencing NF-kappaB activation or ICAM-1 and IL-8 mRNA levels. HSP27 silencing reduced cellular HSP27 levels and HSP27 phosphorylation following TNF stimulation but had no effect on ICAM-1 and IL-8 expression. Our study demonstrates for the first time that MK2 mediates post-transcriptional regulation by p38 MAPK of the TNF-induced expression of ICAM-1 and IL-8 in human lung MVECs, and that this regulation by the p38 MAPK/MK2 pathway is dissociated from HSP27 phosphorylation.
authors.affiliation: Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Su
authors.forename: Lihua
authors.initials: L
authors.lastname: Ao
authors.forename: Ning
authors.initials: N
authors.lastname: Zou
authors.forename: Yong
authors.initials: Y
authors.lastname: Song
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.forename: Guang-Yun
authors.initials: GY
authors.lastname: Cai
authors.forename: David A
authors.initials: DA
authors.lastname: Fullerton
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Meng
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D005786:Gene Expression Regulation; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000276:immunology*; D020935:MAP Kinase Signaling System; D008833:Microcirculation / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018799:Intercellular Adhesion Molecule-1; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C057725:HSPB1 protein, human