title: Glutaredoxin 1 regulates cigarette smoke-mediated lung inflammation through differential modulation of I{kappa}B kinases in mice: impact on histone acetylation.
abstract: Glutaredoxin 1 (Glrx1) is a small dithiol protein that regulates the cellular redox state and redox-dependent signaling pathways via modulation of protein glutathionylation. IkappaB kinase (IKK), an essential enzyme for NF-kappaB activation, can be subjected to S-glutathionylation leading to alteration of its activity. However, the role of Glrx1 in cigarette smoke (CS)-induced lung inflammation and chromatin modifications are not known. We hypothesized that Glrx1 regulates the CS-induced lung inflammation and chromatin modifications via differential regulation of IKKs by S-glutathionylation in mouse lung. Glrx1 knockout (KO) and wild-type (WT) mice were exposed to CS for 3 days and determined the role of Glrx1 in regulation of proinflammatory response in the lung. Neutrophil influx in bronchoalveolar lavage fluid and proinflammatory cytokine release in lung were increased in Glrx1 KO mice compared with WT mice exposed to CS, which was associated with augmented nuclear translocation of RelA/p65 and its phospho-acetylation. Interestingly, phosphorylated and total levels of IKKalpha, but not total and phosphorylated IKKbeta levels, were increased in lungs of Glrx1 KO mice compared with WT mice exposed to CS. Ablation of Glrx1 leads to increased CS-induced IKKbeta glutathionylation rendering it inactive, whereas IKKalpha was activated resulting in increased phospho-acetylation of histone H3 in mouse lung. Thus, targeted disruption of Glrx1 regulates the lung proinflammatory response via histone acetylation specifically by activation of IKKalpha in response to CS exposure. Overall, our study suggests that S-glutathionylation and phosphorylation of IKKalpha plays an important role in histone acetylation on proinflammatory gene promoters and NF-kappaB-mediated abnormal and sustained lung inflammation in pathogenesis of chronic inflammatory lung diseases.
authors.affiliation: Dept. of Environmental Medicine, Univ. of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Sangwoon
authors.initials: S
authors.lastname: Chung
authors.forename: Isaac Kirubakaran
authors.initials: IK
authors.lastname: Sundar
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Ye-Shih
authors.initials: YS
authors.lastname: Ho
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000107:Acetylation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054477:Glutaredoxins / Q000096:biosynthesis / Q000172:deficiency / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D011014:Pneumonia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D012907:Smoking / Q000009:adverse effects*
chemical_list: D054477:Glutaredoxins; D006657:Histones; D016328:NF-kappa B; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D005978:Glutathione
references.citation: Biochemistry. 2001 Nov 27;40(47):14134-42
references.pmid: 11714266
references.citation: Nat Protoc. 2006;1(6):3159-65
references.pmid: 17406579
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1174-86
references.pmid: 18375740
references.citation: Am J Respir Cell Mol Biol. 2008 Jun;38(6):689-98
references.pmid: 18239189
references.citation: J Biol Chem. 2009 Feb 20;284(8):4760-6
references.pmid: 19074435
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 29;103(35):13086-91
references.pmid: 16916935
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8945-50
references.pmid: 15184672
references.citation: J Biol Chem. 2006 Jul 7;281(27):18684-90
references.pmid: 16675465
references.citation: Antioxid Redox Signal. 2008 Apr;10(4):799-811
references.pmid: 18220485
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20820-5
references.pmid: 18093951
references.citation: Free Radic Biol Med. 2008 Dec 15;45(12):1714-22
references.pmid: 18929643
references.citation: Endocrinology. 2009 Mar;150(3):1122-31
references.pmid: 18988672
references.citation: Mol Cells. 2008 May 31;25(3):332-46
references.pmid: 18483468
references.citation: Mol Cell. 2002 Mar;9(3):625-36
references.pmid: 11931769
references.citation: Carcinogenesis. 2006 Apr;27(4):811-9
references.pmid: 16280330
references.citation: J Biol Chem. 2007 Jul 20;282(29):21308-18
references.pmid: 17537731
references.citation: EMBO J. 2002 Dec 2;21(23):6539-48
references.pmid: 12456660
references.citation: EMBO J. 2008 Mar 19;27(6):865-75
references.pmid: 18309294
references.citation: J Biol Chem. 2007 Apr 27;282(17):12467-74
references.pmid: 17324929
references.citation: Free Radic Biol Med. 2007 Nov 1;43(9):1299-312
references.pmid: 17893043
references.citation: Am J Rhinol Allergy. 2009 May-Jun;23(3):288-93
references.pmid: 19490803
references.citation: J Biol Chem. 2007 Jun 22;282(25):18427-18436
references.pmid: 17468103
references.citation: J Cell Biol. 2009 Jan 26;184(2):241-52
references.pmid: 19171757
references.citation: Exp Eye Res. 2009 Dec;89(6):833-9
references.pmid: 19664619
references.citation: Free Radic Biol Med. 2000 May 1;28(9):1405-20
references.pmid: 10924859
references.citation: Free Radic Biol Med. 2009 Jun 1;46(11):1534-42
references.pmid: 19289167
references.citation: Am J Respir Cell Mol Biol. 2009 Apr;40(4):464-73
references.pmid: 18927347
references.citation: Am J Respir Cell Mol Biol. 2007 Feb;36(2):147-51
references.pmid: 16980552
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Jul;291(1):L46-57
references.pmid: 16473865
references.citation: Hum Pathol. 2004 Aug;35(8):1000-7
references.pmid: 15297967
references.citation: Antioxid Redox Signal. 2004 Feb;6(1):63-74
references.pmid: 14713336
references.citation: Science. 1999 Apr 9;284(5412):309-13
references.pmid: 10195894
references.citation: Biochim Biophys Acta. 1998 Dec 8;1436(1-2):245-61
references.pmid: 9838145
references.citation: Trends Biochem Sci. 2001 Mar;26(3):186-90
references.pmid: 11246025
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Feb;292(2):L567-76
references.pmid: 17041012
references.citation: Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):348-66
references.pmid: 15706083
references.citation: Curr Drug Targets. 2006 Jun;7(6):661-8
references.pmid: 16787168
references.citation: Environ Health Perspect. 1985 Dec;64:111-26
references.pmid: 3007083
references.citation: J Exp Biol. 2009 Nov;212(Pt 22):3612-20
references.pmid: 19880721
references.citation: Am J Respir Crit Care Med. 1999 Feb;159(2):473-9
references.pmid: 9927360
references.citation: Oncogene. 2006 Oct 30;25(51):6717-30
references.pmid: 17072324
references.citation: J Mol Cell Cardiol. 2008 Feb;44(2):261-9
references.pmid: 17976641
references.citation: Invest Ophthalmol Vis Sci. 2008 Oct;49(10):4497-505
references.pmid: 18586881
references.citation: Trends Cell Biol. 2009 Aug;19(8):404-13
references.pmid: 19648011
references.citation: Eur Respir J. 2002 Sep;20(3):556-63
references.pmid: 12358328
references.citation: Am J Respir Cell Mol Biol. 2008 Jul;39(1):7-18
references.pmid: 18239191
references.citation: Nature. 2003 Jun 5;423(6940):655-9
references.pmid: 12789342
references.citation: Mol Cell Biol. 2005 Sep;25(18):7966-75
references.pmid: 16135789
references.citation: Curr Med Chem. 2007;14(2):213-22
references.pmid: 17266580
references.citation: Circ Res. 2007 Feb 2;100(2):152-4
references.pmid: 17272816
references.citation: Proc Am Thorac Soc. 2009 May 1;6(3):249-55
references.pmid: 19387025
references.citation: J Biol Chem. 2004 Jan 30;279(5):3563-72
references.pmid: 14597631
references.citation: FASEB J. 2001 Sep;15(11):1865-76
references.pmid: 11532966
references.citation: Am J Pathol. 2009 Jul;175(1):36-45
references.pmid: 19556513
references.citation: Eur J Biochem. 2000 Aug;267(16):4928-44
references.pmid: 10931175
references.citation: Biochem Pharmacol. 2006 Feb 28;71(5):551-64
references.pmid: 16337153
references.citation: Am J Pathol. 2008 May;172(5):1222-37
references.pmid: 18403597
references.citation: Biochim Biophys Acta. 2008 Nov;1780(11):1304-17
references.pmid: 18621099
references.citation: Nat Rev Mol Cell Biol. 2007 Jan;8(1):49-62
references.pmid: 17183360
references.citation: Biochemistry. 1998 Dec 8;37(49):17145-56
references.pmid: 9860827
references.citation: Respir Res. 2006 Oct 25;7:133
references.pmid: 17064412