Acrolein induces heme oxygenase-1 through PKC-delta and PI3K in human bronchial epithelial cells.
Heme oxygenase-1 (HO-1) catalyzes the rate limiting reaction of heme metabolism and plays critical roles in resistance to oxidative stress and other cellular functions. It is well known that HO-1 is induced in response to various stresses; however, the signaling pathways involved remain incompletely elucidated. Acrolein is an alpha,beta-unsaturated aldehyde present in cigarette smoke and also a product of lipid peroxidation. In this investigation we studied HO-1 induction in response to acrolein and determined the signaling pathways involved in human bronchial epithelial cells (HBE1 cells). We demonstrated that acrolein significantly increased the HO-1 mRNA content and promoter activity. Acrolein-mediated HO-1 induction was significantly attenuated by pan-protein kinase C (PKC) inhibitors RO318220, staurosporine, and PKC-delta selective inhibitor rottlerin and PKC-delta small interfering RNA. The HO-1 induction was also decreased by phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin. No significant effects on HO-1 induction were observed with the pretreatment of mitogen-activated protein kinase pathway inhibitors PD98059 (ERK), SB203580 (p38MAPK) and JNKi, and conventional and atypical PKC inhibitors. Furthermore, Nrf2 silencing significantly attenuated the HO-1 induction by acrolein. Inhibition of PKC-delta significantly decreased acrolein-mediated Nrf2 nuclear translocation, though inhibition of PI3K had no effect. Taken together, our results indicate that acrolein up-regulates HO-1 expression through both PKC-delta and PI3K pathways in HBE1 cells; PKC-delta appears to regulate HO-1 induction via modulating Nrf2 nuclear translocation, while PI3K may work through targeting on downstream signaling molecules other than Nrf2.
School of Natural Sciences, University of California, Merced, P.O. Box 2039, Merced, CA 95340, USA.
Hongqiao
H
Zhang
Henry Jay
HJ
Forman
D000171:Acrolein / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering; D014158:Transcription, Genetic / Q000187:drug effects
D000171:Acrolein; D004791:Enzyme Inhibitors; D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051745:Protein Kinase C-delta; D034741:RNA, Small Interfering