Modulation of keratinocyte expression of antioxidants by 4-hydroxynonenal, a lipid peroxidation end product

4-Hydroxynonenal (4-HNE) is a lipid peroxidation end product generated in response to oxidative stress in the skin. Keratinocytes contain an array of antioxidant enzymes which protect against oxidative stress. In these studies, we characterized 4-HNE-induced changes in antioxidant expression in mous...

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Published in:Toxicology and applied pharmacology 2014-03, Vol.275 (2), p.113-121
Main Authors: Zheng, Ruijin, Heck, Diane E., Mishin, Vladimir, Black, Adrienne T., Shakarjian, Michael P., Kong, Ah-Ng Tony, Laskin, Debra L., Laskin, Jeffrey D.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
ALDEHYDES
Aldehydes - pharmacology
Animals
ANTIOXIDANTS
Antioxidants - metabolism
beta-Cyclodextrins - pharmacology
Biological and medical sciences
CATALASE
Caveolae
Caveolae - drug effects
Caveolae - metabolism
Cell Line
CENTRIFUGATION
GLUTATHIONE
Glutathione Transferase - genetics
Glutathione Transferase - metabolism
HEME
Heme oxygenase-1
Heme Oxygenase-1 - genetics
Heme Oxygenase-1 - metabolism
Keratinocytes - drug effects
Keratinocytes - metabolism
Lipid Peroxidation - drug effects
LIPIDS
Medical sciences
Membrane Proteins - genetics
Membrane Proteins - metabolism
MEMBRANES
MESSENGER-RNA
MICE
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 3 - genetics
Mitogen-Activated Protein Kinase 3 - metabolism
MOLECULES
NAD(P)H Dehydrogenase (Quinone) - genetics
NAD(P)H Dehydrogenase (Quinone) - metabolism
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Nrf2
OXIDATION
Oxidative Stress - drug effects
p38 Mitogen-Activated Protein Kinases - genetics
p38 Mitogen-Activated Protein Kinases - metabolism
PHOSPHOTRANSFERASES
RNA, Messenger - genetics
RNA, Messenger - metabolism
SACCHAROSE
Signal Transduction
SKIN
Stress proteins
TIME DEPENDENCE
Toxicology
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Summary:4-Hydroxynonenal (4-HNE) is a lipid peroxidation end product generated in response to oxidative stress in the skin. Keratinocytes contain an array of antioxidant enzymes which protect against oxidative stress. In these studies, we characterized 4-HNE-induced changes in antioxidant expression in mouse keratinocytes. Treatment of primary mouse keratinocytes and PAM 212 keratinocytes with 4-HNE increased mRNA expression for heme oxygenase-1 (HO-1), catalase, NADPH:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) A1-2, GSTA3 and GSTA4. In both cell types, HO-1 was the most sensitive, increasing 86–98 fold within 6h. Further characterization of the effects of 4-HNE on HO-1 demonstrated concentration- and time-dependent increases in mRNA and protein expression which were maximum after 6h with 30μM. 4-HNE stimulated keratinocyte Erk1/2, JNK and p38 MAP kinases, as well as PI3 kinase. Inhibition of these enzymes suppressed 4-HNE-induced HO-1 mRNA and protein expression. 4-HNE also activated Nrf2 by inducing its translocation to the nucleus. 4-HNE was markedly less effective in inducing HO-1 mRNA and protein in keratinocytes from Nrf2−/− mice, when compared to wild type mice, indicating that Nrf2 also regulates 4-HNE-induced signaling. Western blot analysis of caveolar membrane fractions isolated by sucrose density centrifugation demonstrated that 4-HNE-induced HO-1 is localized in keratinocyte caveolae. Treatment of the cells with methyl-β-cyclodextrin, which disrupts caveolar structure, suppressed 4-HNE-induced HO-1. These findings indicate that 4-HNE modulates expression of antioxidant enzymes in keratinocytes, and that this can occur by different mechanisms. Changes in expression of keratinocyte antioxidants may be important in protecting the skin from oxidative stress. [Display omitted] •Lipid peroxidation generates 4-hydroxynonenal, a reactive aldehyde.•4-HNE induces antioxidant proteins in mouse keratinocytes.•Induction of antioxidant proteins is regulated via MAP kinases, Nrf2 and caveolae.•4-HNE is an effective signaling molecule in keratinocytes.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2014.01.001