HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells.
Heme oxygenase-1 (HO-1) is a key cytoprotective enzyme and an established marker of oxidative stress. Increased HO-1 expression has been found in the resident macrophages in the alveolar spaces of smokers. The lipid peroxidation product 4-hydroxynonenal (HNE) is also increased in the bronchial and alveolar epithelium in response to cigarette smoke. This suggests a link between a chronic environmental stress, HNE formation, and HO-1 induction. HNE is both an agent of oxidative stress in vivo and a potent cell signaling molecule. We hypothesize that HNE acts as an endogenously produced pulmonary signaling molecule that elicits an adaptive response culminating in the induction of HO-1. Here we demonstrate that HNE increases HO-1 mRNA, protein, and activity in pulmonary epithelial cells and identify ERK as a key pathway involved. Treatment with HNE increased ERK phosphorylation, c-Fos protein, JNK phosphorylation, c-Jun phosphorylation, and AP-1 binding. Whereas inhibiting the ERK pathway with the MEK inhibitor PD98059 significantly decreased HNE-mediated ERK phosphorylation, c-Fos protein induction, AP-1 binding, and HO-1 protein induction, inhibition of the ERK pathway had no effect on HNE-induced HO-1 mRNA. This suggests that ERK is involved in the increase in HO-1 through regulation of translation rather than transcription.
Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Karen E
KE
Iles
Dale A
DA
Dickinson
Amanda F
AF
Wigley
Nathan E
NE
Welty
Volker
V
Blank
Henry Jay
HJ
Forman
D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects* / Q000502:physiology; D004848:Epithelium / Q000187:drug effects* / Q000201:enzymology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000187:drug effects* / Q000378:metabolism; D051547:Heme Oxygenase-1; D008168:Lung / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D014176:Protein Biosynthesis; D012333:RNA, Messenger; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000447:Aldehydes; D000873:Anthracenes; D015853:Cysteine Proteinase Inhibitors; D012333:RNA, Messenger; C432165:pyrazolanthrone; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases; C027576:4-hydroxy-2-nonenal