期刊
BLOOD
卷 116, 期 26, 页码 5795-5802出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-03-273094
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资金
- l'Agence Nationale de la Recherche
- Arthritis Fondation Courtin
- Vaincre la mucoviscidose
- Comite Mixte de Cooperation Universitaire franco-tunisien
- Accord Inserm/DGRST
- Inserm and Centre National de la Recherche Scientifique
- National Institutes of Health [P30 HD03352, P01 HL088594, R01 HL087950]
Neutrophils play a key role in host defense by releasing reactive oxygen species ( ROS). However, excessive ROS production by neutrophil nicotinamide adenine dinucleotide phosphate ( NADPH) oxidase can damage bystander tissues, thereby contributing to inflammatory diseases. Tumor necrosis factor-alpha ( TNF-alpha), a major mediator of inflammation, does not activate NADPH oxidase but induces a state of hyperresponsiveness to subsequent stimuli, an action known as priming. The molecular mechanisms by which TNF-alpha primes the NADPH oxidase are unknown. Here we show that Pin1, a unique cis-trans prolyl isomerase, is a previously unrecognized regulator of TNF-alpha-induced NADPH oxidase hyperactivation. We first showed that Pin1 is expressed in neutrophil cytosol and that its activity is markedly enhanced by TNF-alpha. Inhibition of Pin1 activity with juglone or with a specific peptide inhibitor abrogated TNF-alpha-induced priming of neutrophil ROS production induced by N-formylmethionyl-leucyl-phenylalanine peptide (fMLF). TNF-alpha enhanced fMLF-induced Pin1 and p47phox translocation to the membranes and juglone inhibited this process. Pin1 binds to p47phox via phosphorylated Ser345, thereby inducing conformational changes that facilitate p47phox phosphorylation on other sites by protein kinase C. These findings indicate that Pin1 is critical for TNF-alpha induced priming of NADPH oxidase and for excessive ROS production. Pin1 inhibition could potentially represent a novel anti-inflammatory strategy. (Blood. 2010; 116(26): 5795-5802)
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