title: Heat shock protein-70 mediates the cytoprotective effect of carbon monoxide: involvement of p38 beta MAPK and heat shock factor-1.
abstract: Carbon monoxide (CO), a product of heme oxygenase activity, exerts antiapoptotic and anti-inflammatory effects in vitro and in vivo. The anti-inflammatory effects of CO involve the inhibition of TNF-alpha expression and the enhancement of IL-10 production, resulting in reduced mortality after endotoxin challenge. In this study we demonstrate for the first time that the protective effects of CO involve the increased expression of the 70-kDa inducible heat shock protein (Hsp70) in murine lung endothelial cells and fibroblasts. The p38beta MAPK mediated the effects of CO on cytoprotection and Hsp70 regulation. Suppression of Hsp70 expression and/or genetic deletion of heat shock factor-1, the principle transcriptional regulator of Hsp70, attenuated the cytoprotective and immunomodulatory effects of CO in mouse lung cells and in vivo. These data provide a novel mechanism for the protective effects of CO and underscore a potential application of this gaseous molecule in anti-inflammatory therapies.
authors.affiliation: Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.forename: Jinglan
authors.initials: J
authors.lastname: Zhang
authors.forename: Gee Young
authors.initials: GY
authors.lastname: Suh
authors.forename: Ivor J
authors.initials: IJ
authors.lastname: Benjamin
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002248:Carbon Monoxide / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D002478:Cells, Cultured; D019610:Cytoprotection / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity; D008168:Lung / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D048290:Mitogen-Activated Protein Kinase 11 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012772:Shock, Septic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D015996:Survival Rate; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D008070:Lipopolysaccharides; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D002248:Carbon Monoxide; D048290:Mitogen-Activated Protein Kinase 11