Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo.

Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. Research Abstract Details 

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Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. Abstract Text:

Nima M Gharavi,Jackelyn A Alva,Kevin P Mouillesseaux,Chi Lai,Michael Yeh,Winnie Yeung,Jaclyn Johnson,Wan Lam Szeto,Longsheng Hong,Michael Fishbein,Lai Wei,Lawrence M Pfeffer,Judith A Berliner,Nima M Gharavi,Jackelyn A Alva,Kevin P Mouillesseaux,Chi Lai,Michael Yeh,Winnie Yeung,Jaclyn Johnson,Wan Lam Szeto,Longsheng Hong,Michael Fishbein,Lai Wei,Lawrence M Pfeffer,Judith A Berliner,

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and its component phospholipid, 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine, induce endothelial cells (EC) to synthesize chemotactic factors, such as interleukin 8 (IL-8). Previously, we demonstrated a role for c-Src kinase activation in Ox-PAPC-induced IL-8 transcription. In this study, we have examined the mechanism regulating IL-8 transcription by Ox-PAPC downstream of c-Src. Our findings demonstrate an important role for JAK2 in the regulation of IL-8 transcription by Ox-PAPC. Treatment of human aortic EC with Ox-PAPC and 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine induced a rapid yet sustained activation of JAK2; activation of JAK2 by Ox-PAPC was dependent on c-Src kinase activity. Furthermore, pretreatment with selective JAK2 inhibitors significantly reduced Ox-PAPC-induced IL-8 transcription. In previous studies, we also demonstrated activation of STAT3 by Ox-PAPC. Here we provide evidence that STAT3 activation by Ox-PAPC is dependent on JAK2 activation and that STAT3 activation regulates IL-8 transcription by Ox-PAPC in human EC. Transfection with small interfering RNA against STAT3 significantly reduced Ox-PAPC-induced IL-8 transcription. Using chromatin immunoprecipitation assays, we demonstrated binding of activated STAT3 to the sequence flanking the consensus gamma-interferon activation sequence (GAS) in the IL-8 promoter; site-directed mutagenesis of GAS inhibited IL-8 transcription by Ox-PAPC. Finally, these studies demonstrate a role for STAT3 activation in atherosclerosis in vivo. We found increased staining for activated STAT3 in the inflammatory regions of human atherosclerotic lesions and reduced fatty streak formation in EC-specific STAT3 knock-out mice on the atherogenic diet. Taken together, these data demonstrate an important role for the JAK2/STAT3 pathway in Ox-PAPC-induced IL-8 transcription in vitro and in atherosclerosis in vivo.

Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. Publishing Authors By Initials

NM Gharavi,JA Alva,KP Mouillesseaux,C Lai,M Yeh,W Yeung,J Johnson,WL Szeto,L Hong,M Fishbein,L Wei,LM Pfeffer,JA Berliner,NM Gharavi,JA Alva,KP Mouillesseaux,C Lai,M Yeh,W Yeung,J Johnson,WL Szeto,L Hong,M Fishbein,L Wei,LM Pfeffer,JA Berliner,

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Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 31460-8

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 28

MONTH: 08

YEAR: 2007

Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. Information

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LANGUAGE: eng

NlmUniqueID: 2985121

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Grant and Affiliation Information for Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo.

AFFILIATION: Division of Cardiology, Department of Medicine, Department of Pathology, Molecular Biology Institute, UCLA, Los Angeles, California 90095, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: HL30568

ACRONYM: HL

MEDLINETA: J Biol Chem

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