title: p53 mediates cigarette smoke-induced apoptosis of pulmonary endothelial cells: inhibitory effects of macrophage migration inhibitor factor.
abstract: Exposure to cigarette smoke (CS) is the most common cause of emphysema, a debilitating pulmonary disease histopathologically characterized by the irreversible destruction of lung architecture. Mounting evidence links enhanced endothelial apoptosis causally to the development of emphysema. However, the molecular determinants of human endothelial cell apoptosis and survival in response to CS are not fully defined. Such determinants could represent clinically relevant targets for intervention. We show here that CS extract (CSE) triggers the death of human pulmonary macrovascular endothelial cells (HPAECs) through a caspase 9-dependent apoptotic pathway. Exposure to CSE results in the increased expression of p53 in HPAECs. Using the p53 inhibitor, pifithrin-α (PFT-α), and RNA interference (RNAi) directed at p53, we demonstrate that p53 function and expression are required for CSE-mediated apoptosis. The expression of macrophage migration inhibitory factor (MIF), an antiapoptotic cytokine produced by HPAECs, also increases in response to CSE exposure. The addition of recombinant human MIF prevents cell death from exposure to CSE. Further, the suppression of MIF or its receptor/binding partner, Jun activation domain-binding protein 1 (Jab-1), with RNAi enhances the sensitivity of human pulmonary endothelial cells to CSE via a p53-dependent (PFT-α-inhibitable) pathway. Finally, we demonstrate that MIF is a negative regulator of p53 expression in response to CSE, placing MIF upstream of p53 as an antagonist of CSE-induced apoptosis. We conclude that MIF can protect human vascular endothelium from the toxic effects of CSE via the antagonism of p53-mediated apoptosis.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA. rdamico1@jhmi.edu
authors.forename: Rachel
authors.initials: R
authors.lastname: Damico
authors.forename: Tiffany
authors.initials: T
authors.lastname: Simms
authors.forename: Bo S
authors.initials: BS
authors.lastname: Kim
authors.forename: Zenar
authors.initials: Z
authors.lastname: Tekeste
authors.forename: Henry
authors.initials: H
authors.lastname: Amankwan
authors.forename: Mahendra
authors.initials: M
authors.lastname: Damarla
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
mesh_terms: D017209:Apoptosis; D000075686:COP9 Signalosome Complex; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000187:drug effects*; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008263:Macrophage Migration-Inhibitory Factors; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D053453:Caspase 9
references.citation: Mol Cell Biol. 2000 Nov;20(22):8458-67
references.pmid: 11046142
references.citation: J Biol Chem. 2003 Apr 18;278(16):14219-29
references.pmid: 12480939
references.citation: Clin Chim Acta. 2008 Nov;397(1-2):48-50
references.pmid: 18692035
references.citation: Proc Am Thorac Soc. 2006 Nov;3(8):713-7
references.pmid: 17065379
references.citation: Proc Am Thorac Soc. 2006 Aug;3(6):512-6
references.pmid: 16921132
references.citation: J Immunol. 2008 Apr 1;180(7):4668-78
references.pmid: 18354190
references.citation: Respir Res. 2005 Feb 10;6:14
references.pmid: 15705190
references.citation: J Biol Chem. 2003 May 2;278(18):15465-8
references.pmid: 12637507
references.citation: Arthritis Rheum. 2002 Sep;46(9):2402-9
references.pmid: 12355488
references.citation: Am J Respir Crit Care Med. 2008 Aug 1;178(3):240-7
references.pmid: 18511705
references.citation: Am J Respir Crit Care Med. 2005 Apr 1;171(7):734-42
references.pmid: 15563631
references.citation: Trends Biochem Sci. 2008 Dec;33(12):592-600
references.pmid: 18926707
references.citation: Lancet. 2007 Sep 1;370(9589):765-73
references.pmid: 17765526
references.citation: Science. 1999 Sep 10;285(5434):1733-7
references.pmid: 10481009
references.citation: J Biol Chem. 2004 Oct 8;279(41):43013-8
references.pmid: 15299027
references.citation: Eur Respir J. 2005 Feb;25(2):250-8
references.pmid: 15684288
references.citation: Circulation. 2005 Mar 22;111(11):1407-14
references.pmid: 15781752
references.citation: Dev Cell. 2006 May;10(5):549-61
references.pmid: 16678772
references.citation: Proc Am Thorac Soc. 2006 Aug;3(6):510
references.pmid: 16921130
references.citation: Nature. 2009 Apr 30;458(7242):1127-30
references.pmid: 19407794
references.citation: J Exp Med. 1999 Nov 15;190(10):1375-82
references.pmid: 10562313
references.citation: Respir Res. 2006 Mar 30;7:53
references.pmid: 16571143
references.citation: Arch Toxicol. 2006 Jun;80(6):328-36
references.pmid: 16341695
references.citation: EMBO J. 2001 Apr 2;20(7):1630-9
references.pmid: 11285227
references.citation: Apoptosis. 2007 May;12(5):887-96
references.pmid: 17453158
references.citation: Cell Death Differ. 2007 Mar;14(3):447-52
references.pmid: 16946732
references.citation: Am J Respir Cell Mol Biol. 2002 Jan;26(1):152-9
references.pmid: 11751215
references.citation: J Biol Chem. 2005 Jul 22;280(29):27345-55
references.pmid: 15886205
references.citation: Biochemistry (Mosc). 2000 Jan;65(1):41-8
references.pmid: 10702639
references.citation: Am J Respir Crit Care Med. 2007 Apr 1;175(7):676-85
references.pmid: 17255567
references.citation: Am J Respir Cell Mol Biol. 2003 Jul;29(1):88-97
references.pmid: 12600822
references.citation: J Clin Invest. 2000 Dec;106(11):1311-9
references.pmid: 11104784
references.citation: Cell Signal. 2008 Jan;20(1):230-40
references.pmid: 18006276
references.citation: J Biol Chem. 2004 Jul 16;279(29):30195-201
references.pmid: 15145929
references.citation: Am J Respir Crit Care Med. 2006 Jun 1;173(11):1222-8
references.pmid: 16514110
references.citation: Crit Care Med. 2002 May;30(5 Suppl):S263-7
references.pmid: 12004246
references.citation: Chest. 2004 Feb;125(2):626-32
references.pmid: 14769747
references.citation: Nature. 2000 Nov 9;408(6809):211-6
references.pmid: 11089976
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L897-908
references.pmid: 16361360
references.citation: J Biol Chem. 2002 Jan 18;277(3):2302-10
references.pmid: 11704659
references.citation: Chest. 1999 Mar;115(3):829-35
references.pmid: 10084499
references.citation: J Cell Biochem. 2008 Mar 1;103(4):1219-30
references.pmid: 17879958
references.citation: J Biol Chem. 2008 Jul 18;283(29):20383-96
references.pmid: 18502749
references.citation: Am J Respir Cell Mol Biol. 2008 Jul;39(1):77-85
references.pmid: 18239193
references.citation: Indoor Air. 2004 Dec;14(6):421-4
references.pmid: 15500635