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Published ahead of print on November 29, 2007, doi:10.1165/rcmb.2007-0260OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 4, April 2008, 483-490

A more recent version of this article appeared on April 1, 2008
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Submitted on July 9, 2007
Revised on November 29, 2007

Acrolein Induces Heme Oxygenase-1 Through PKC-{delta} and PI3K in Human Bronchial Epithelial Cells

Hongqiao Zhang1 and Henry Jay Forman1*

1 University of California at Merced, School of Natural Science, Merced, CA, USA

* To whom correspondence should be addressed. E-mail: hjforman{at}gmail.com.

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 remains 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-PKC inhibitors RO318220, staurosporine, and PKC-{delta} selective inhibitor rottlerin and PKC-{delta} siRNA. The HO-1 induction was also decreased by PI3K inhibitors LY294002 and wortmannin. No significant effects on HO-1 induction were observed with the pretreatment of MAPK 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 upregulates 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.




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