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PMID: 19720622 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

NF-E2-related factor 2 regulates the stress response to UVA-1-oxidized phospholipids in skin cells.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology ·Vol. 24 ·No. 1 ·2010-01-00 ·Pages 39-48

Gruber F, Mayer H, Lengauer B, Mlitz V, Sanders JM, Kadl A, Bilban M, de Martin R, Wagner O, Kensler TW, Yamamoto M, Leitinger N, Tschachler E

Abstract

Long-wavelength ultraviolet (UVA-1) radiation causes oxidative stress that modifies cellular molecules. To defend themselves against noxious oxidation products, skin cells produce detoxifying enzymes and antioxidants. We have recently shown that UVA-1 oxidized the abundant membrane phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), which then induced the stress-response protein heme oxygenase 1 (HO-1) in dermal fibroblasts. Here we examined the effects of UVA-1- and UV-oxidized phospholipids on global gene expression in human dermal fibroblasts and keratinocytes. We identified a cluster of genes that were coinduced by UVA-1-oxidized PAPC and UVA-1 radiation. The cluster included HO-1, glutamate-cysteine ligase modifier subunit, aldo-keto reductases-1-C1 and -C2, and IL-8. These genes are members of the cellular stress response system termed "antioxidant response." Accordingly, the regulatory regions of all of these genes contain binding sites for NF-E2-related factor 2 (NRF2), a major regulator of the antioxidant response. Both UVA-1 irradiation and treatment with oxidized lipids led to increased nuclear accumulation and DNA binding of NRF2. Silencing and deficiency of NRF2 suppressed the antioxidant response. Taken together, our data show that UVA-1-mediated lipid oxidation induces expression of antioxidant response genes, which is dependent on the redox-regulated transcription factor NRF2. Our findings suggest a different view on UV-generated lipid mediators that were commonly regarded as detrimental

MeSH Terms
Animals Antioxidants/metabolism Base Sequence Cells, Cultured Fibroblasts/metabolism,radiation effects Gene Expression/radiation effects Glutamate-Cysteine Ligase/biosynthesis Heme Oxygenase-1/biosynthesis Humans Keratinocytes/metabolism,radiation effects Male Mice Mice, Inbred C57BL Mice, Knockout Multigene Family/radiation effects NF-E2-Related Factor 2/antagonists & inhibitors,deficiency,genetics,metabolism Oxidation-Reduction Oxidative Stress/radiation effects Phospholipids/metabolism,radiation effects Promoter Regions, Genetic RNA, Small Interfering/genetics Skin/cytology,metabolism,radiation effects Ultraviolet Rays
Chemicals
Antioxidants NF-E2-Related Factor 2 NFE2L2 protein, human Nfe2l2 protein, mouse Phospholipids RNA, Small Interfering Heme Oxygenase-1 Glutamate-Cysteine Ligase
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Gruber Florian
Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
Mayer Herbert
Lengauer Barbara
Mlitz Veronika
Sanders John M
Kadl Alexandra
Bilban Martin
de Martin Rainer
Wagner Oswald
Kensler Thomas W
Yamamoto Masayuki
Leitinger Norbert
Tschachler Erwin
References (74)
74 references, click to expand
  1. Activation of the Nrf2-ARE signaling pathway: a promising strategy in cancer prevention.
    Bioessays. 2006 Feb;28(2):169-81 PMID: 16435293
  2. A new mathematical model for relative quantification in real-time RT-PCR.
    Nucleic Acids Res. 2001 May 1;29(9):e45 PMID: 11328886
  3. The unfolded protein response is an important regulator of inflammatory genes in endothelial cells.
    Arterioscler Thromb Vasc Biol. 2006 Nov;26(11):2490-6 PMID: 16931790
  4. UVA-1 Phototherapy.
    Photodermatol Photoimmunol Photomed. 2005 Apr;21(2):103-8 PMID: 15752130
  5. Let the sun shine in: mechanisms and potential for therapeutics in skin photodamage.
    Curr Opin Investig Drugs. 2007 May;8(5):390-400 PMID: 17520868
  6. Induction of AKR1C2 by phase II inducers: identification of a distal consensus antioxidant response element regulated by NRF2.
    Mol Pharmacol. 2006 May;69(5):1662-72 PMID: 16478829
  7. Ultraviolet B radiation generates platelet-activating factor-like phospholipids underlying cutaneous damage.
    J Biol Chem. 2005 Oct 21;280(42):35448-57 PMID: 16115894
  8. Anti-inflammatory properties of lipid oxidation products.
    J Mol Med (Berl). 2003 Oct;81(10):613-26 PMID: 13679995
  9. Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects.
    Prostaglandins Other Lipid Mediat. 2008 Dec;87(1-4):1-8 PMID: 18555720
  10. Ox-PAPC activation of PMET system increases expression of heme oxygenase-1 in human aortic endothelial cell.
    J Lipid Res. 2009 Feb;50(2):265-74 PMID: 18757839
  11. Photooxidation generates biologically active phospholipids that induce heme oxygenase-1 in skin cells.
    J Biol Chem. 2007 Jun 8;282(23):16934-41 PMID: 17449870
  12. Oxidized phospholipids as modulators of inflammation in atherosclerosis.
    Curr Opin Lipidol. 2003 Oct;14(5):421-30 PMID: 14501580
  13. Human glutamate cysteine ligase gene regulation through the electrophile response element.
    Free Radic Biol Med. 2004 Oct 15;37(8):1152-9 PMID: 15451055
  14. Cyclopentenone prostaglandins as potential inducers of phase II detoxification enzymes. 15-deoxy-delta(12,14)-prostaglandin j2-induced expression of glutathione S-transferases.
    J Biol Chem. 2000 Apr 14;275(15):11291-9 PMID: 10753940
  15. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository.
    Nucleic Acids Res. 2002 Jan 1;30(1):207-10 PMID: 11752295
  16. Ultraviolet-A1 irradiation decreases clinical disease activity and autoantibodies in patients with systemic lupus erythematosus.
    Clin Exp Rheumatol. 1994 Mar-Apr;12(2):129-35 PMID: 8039279
  17. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements.
    Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22 PMID: 9240432
  18. Solar ultraviolet A radiation: an oxidizing skin carcinogen that activates heme oxygenase-1.
    Antioxid Redox Signal. 2004 Oct;6(5):835-40 PMID: 15345143
  19. Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products.
    Biochem J. 2004 Mar 1;378(Pt 2):373-82 PMID: 14616092
  20. The aryl hydrocarbon receptor is activated by modified low-density lipoprotein.
    Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1412-7 PMID: 17227852
  21. Small Maf proteins serve as transcriptional cofactors for keratinocyte differentiation in the Keap1-Nrf2 regulatory pathway.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6379-84 PMID: 15087497
  22. Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers.
    Mutat Res. 2004 Nov 2;555(1-2):133-48 PMID: 15476857
  23. UVA radiation-induced oxidative damage to lipids and proteins in vitro and in human skin fibroblasts is dependent on iron and singlet oxygen.
    Free Radic Biol Med. 1995 Apr;18(4):721-30 PMID: 7750796
  24. Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo.
    J Biol Chem. 1997 May 23;272(21):13597-607 PMID: 9153208
  25. Induction of phase 2 genes by sulforaphane protects retinal pigment epithelial cells against photooxidative damage.
    Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10446-51 PMID: 15229324
  26. Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms.
    Arch Biochem Biophys. 2007 Aug 15;464(2):241-50 PMID: 17537398
  27. The reactive oxygen species--and Michael acceptor-inducible human aldo-keto reductase AKR1C1 reduces the alpha,beta-unsaturated aldehyde 4-hydroxy-2-nonenal to 1,4-dihydroxy-2-nonene.
    J Biol Chem. 2001 Jan 26;276(4):2890-7 PMID: 11060293
  28. Nox1-based NADPH oxidase is the major source of UVA-induced reactive oxygen species in human keratinocytes.
    J Invest Dermatol. 2008 Jan;128(1):214-22 PMID: 17611574
  29. Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2.
    Am J Pathol. 2006 Jun;168(6):1960-74 PMID: 16723711
  30. Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids.
    Proc Natl Acad Sci U S A. 2006 Aug 22;103(34):12741-6 PMID: 16912112
  31. Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.
    Proc Natl Acad Sci U S A. 2007 May 22;104(21):8851-6 PMID: 17502624
  32. Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3.
    J Biol Chem. 2007 Jan 26;282(4):2529-37 PMID: 17127771
  33. Ultraviolet A irradiation induces NF-E2-related factor 2 activation in dermal fibroblasts: protective role in UVA-induced apoptosis.
    J Invest Dermatol. 2005 Apr;124(4):825-32 PMID: 15816842
  34. Toucan: deciphering the cis-regulatory logic of coregulated genes.
    Nucleic Acids Res. 2003 Mar 15;31(6):1753-64 PMID: 12626717
  35. Oxidized phospholipids stimulate angiogenesis via autocrine mechanisms, implicating a novel role for lipid oxidation in the evolution of atherosclerotic lesions.
    Circ Res. 2006 Oct 13;99(8):900-8 PMID: 16973904
  36. Thyroid hormone responsive genes in cultured human fibroblasts.
    J Clin Endocrinol Metab. 2005 Feb;90(2):936-43 PMID: 15507505
  37. Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.
    J Biol Chem. 2002 Nov 8;277(45):42769-74 PMID: 12198130
  38. DAVID: Database for Annotation, Visualization, and Integrated Discovery.
    Genome Biol. 2003;4(5):P3 PMID: 12734009
  39. Nrf2-deficient female mice develop lupus-like autoimmune nephritis.
    Kidney Int. 2001 Oct;60(4):1343-53 PMID: 11576348
  40. Nrf transcription factors in keratinocytes are essential for skin tumor prevention but not for wound healing.
    Mol Cell Biol. 2006 May;26(10):3773-84 PMID: 16648473
  41. 5 alpha-reductase activity in the human hair follicle concentrates in the dermal papilla.
    Arch Dermatol Res. 1998 Mar;290(3):126-32 PMID: 9558487
  42. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory.
    J Exp Med. 2004 Dec 6;200(11):1359-70 PMID: 15583011
  43. Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts.
    Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2607-10 PMID: 8146161
  44. Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2).
    Mol Cell Biol. 2004 Jan;24(1):36-45 PMID: 14673141
  45. Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element.
    Biochem Biophys Res Commun. 1999 Aug 11;261(3):661-8 PMID: 10441483
  46. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis.
    Mol Cell Biol. 2007 Oct;27(20):7188-97 PMID: 17709388
  47. Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers.
    Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2040-5 PMID: 14764894
  48. TOUCAN 2: the all-inclusive open source workbench for regulatory sequence analysis.
    Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W393-6 PMID: 15980497
  49. Oxidized phospholipids increase interleukin 8 (IL-8) synthesis by activation of the c-src/signal transducers and activators of transcription (STAT)3 pathway.
    J Biol Chem. 2004 Jul 16;279(29):30175-81 PMID: 15143062
  50. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound.
    Mol Cell Biol. 2002 Aug;22(15):5492-505 PMID: 12101242
  51. Distinguishing modes of cell death using the ImageStream multispectral imaging flow cytometer.
    Cytometry A. 2004 Jun;59(2):237-45 PMID: 15170603
  52. Butylhydroquinone protects cells genetically deficient in glutathione biosynthesis from arsenite-induced apoptosis without significantly changing their prooxidant status.
    Toxicol Sci. 2005 Oct;87(2):365-84 PMID: 16014739
  53. Activation of the Nrf2/antioxidant response pathway increases IL-8 expression.
    Eur J Immunol. 2005 Nov;35(11):3258-67 PMID: 16220540
  54. Quantitative measurement of nuclear translocation events using similarity analysis of multispectral cellular images obtained in flow.
    J Immunol Methods. 2006 Apr 20;311(1-2):117-29 PMID: 16563425
  55. Mechanism of heme oxygenase-1 gene activation by cadmium in MCF-7 mammary epithelial cells. Role of p38 kinase and Nrf2 transcription factor.
    J Biol Chem. 2000 Sep 8;275(36):27694-702 PMID: 10874044
  56. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.
    J Clin Invest. 1997 Sep 1;100(5):1209-16 PMID: 9276739
  57. Signaling pathways involved in OxPAPC-induced pulmonary endothelial barrier protection.
    Microvasc Res. 2007 May;73(3):173-81 PMID: 17292425
  58. Identifying biological themes within lists of genes with EASE.
    Genome Biol. 2003;4(10):R70 PMID: 14519205
  59. Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. Formation of these oxidized phospholipids in response to interleukin-1beta.
    J Biol Chem. 2002 Mar 1;277(9):7271-81 PMID: 11751881
  60. Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations.
    Arthritis Rheum. 2005 Jan;52(1):192-200 PMID: 15641060
  61. Effects of solar radiation on cutaneous detoxification pathways.
    J Photochem Photobiol B. 2001 Oct;63(1-3):61-9 PMID: 11684452
  62. The cyclopentenone product of lipid peroxidation, 15-A(2t)-isoprostane (8-isoprostaglandin A(2)), is efficiently conjugated with glutathione by human and rat glutathione transferase A4-4.
    Chem Res Toxicol. 2002 Sep;15(9):1114-8 PMID: 12230403
  63. Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway.
    Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H770-6 PMID: 17468336
  64. Cyclooxygenase dependent release of heme from microsomal hemeproteins correlates with induction of heme oxygenase 1 transcription in human fibroblasts.
    Free Radic Biol Med. 1999 Mar;26(5-6):511-7 PMID: 10218639
  65. UVA and UVB radiation differentially regulate vascular endothelial growth factor expression in keratinocyte-derived cell lines and in human keratinocytes.
    Photochem Photobiol. 1999 Oct;70(4):674-9 PMID: 10546564
  66. The transcriptional activation program of human neutrophils in skin lesions supports their important role in wound healing.
    J Immunol. 2004 Jun 15;172(12):7684-93 PMID: 15187151
  67. Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment.
    Antioxid Redox Signal. 2007 Dec;9(12):2119-37 PMID: 17767398
  68. Molecular mechanisms of Nrf2-mediated antioxidant response.
    Mol Carcinog. 2009 Feb;48(2):91-104 PMID: 18618599
  69. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults.
    Mutat Res. 2008 Jul-Aug;659(1-2):31-9 PMID: 18164232
  70. Epoxycyclopentenone-containing oxidized phospholipids restore endothelial barrier function via Cdc42 and Rac.
    Circ Res. 2004 Oct 29;95(9):892-901 PMID: 15472119
  71. Deciphering regulatory patterns of inflammatory gene expression from interleukin-1-stimulated human endothelial cells.
    Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1192-8 PMID: 15130917
  72. Separation of peroxidation products of diacyl-phosphatidylcholines by reversed-phase liquid chromatography-mass spectrometry.
    Biomed Chromatogr. 2005 Mar;19(2):129-37 PMID: 15558686
  73. Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils.
    Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12010-5 PMID: 10518567
  74. Heme oxygenase-1: unleashing the protective properties of heme.
    Trends Immunol. 2003 Aug;24(8):449-55 PMID: 12909459
Article Info
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Abbr.
FASEB J
ISSN
1530-6860
DOI
10.1096/fj.09-133520
Published
2010-01-00
Epub
2009-00-31
Pages
39-48
Language
English
Region
United States
NLM ID
8804484
PMCID
PMC2797031
Subset
IM
Grants
NCI NIH HHS · R01 CA094076 · United States
NHLBI NIH HHS · R01 HL084422 · United States
NHLBI NIH HHS · R01 HL084422-01 · United States
External Links
PubMed source DOI: 10.1096/fj.09-133520 PMC Full Text View journal details
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