Resveratrol attenuates C5a-induced inflammatory responses in vitro and in vivo by inhibiting phospholipase D and sphingosine kinase activities

被引:56
作者
Issuree, Priya D. A. [1 ]
Pushparaj, Peter N. [1 ,4 ]
Pervaiz, Shazib [1 ,2 ,3 ,5 ]
Melendez, Alirio J. [1 ,2 ,4 ]
机构
[1] Natl Univ Singapore, Dept Physiol, Yong Loo Lin Sch Med, Singapore 117597, Singapore
[2] Natl Univ Singapore, NUS Grad Sch Integrat Sci & Engn, Singapore 117597, Singapore
[3] Natl Univ Singapore, Duke NUS Grad Med Sch, Singapore 117597, Singapore
[4] Univ Glasgow, Glasgow Biomed Res Ctr, Glasgow, Lanark, Scotland
[5] Singapore Massachusetts Inst Technol, Singapore, Singapore
基金
英国医学研究理事会;
关键词
infl131ammation; neutrophil migration; oxidative burst; chemotaxis; ERK1/2; anaphylatoxin; ACTIVATED PROTEIN-KINASE; SIGNAL-REGULATED KINASE; C5A DELAYS APOPTOSIS; FC-GAMMA-RI; NF-KAPPA-B; HUMAN-NEUTROPHILS; PHOSPHATIDIC-ACID; TNF-ALPHA; KEY ROLE; OXIDATIVE BURST;
D O I
10.1096/fj.09-130542
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The anti-inflammatory activity of the phytoalexin resveratrol (RSV) was evaluated in C5 anaphylatoxin (C5a)-stimulated primary neutrophils and in a mouse model of acute peritonitis. Pretreatment of human and mouse neutrophils with RSV significantly blocked oxidative burst, leukocyte migration, degranulation, and inflammatory cytokine production. The anti-inflammatory activity of RSV was a function of inhibition of sphingosine kinase (SphK) activity (IC50 similar to 20 mu M) within 5 min of exposure, its membrane localization, and SphK1-mediated Ca2+ release. As an experimental control, the SphK1 pharmacological inhibitor N,N-dimethyl sphingosine (DMS) was used to compare the inhibitory effect of RSV. We also provide evidence that the SphK inhibitory effect of RSV was mediated via its ability to block phospholipase D (PLD) activity and membrane recruitment. Furthermore, RSV blocked ERK1/2 phosphorylation, which functioned independently of SphK1 in this study. To provide in vivo relevance to these data, C5a-induced model of acute peritonitis was established, and the effects of prior injection of RSV were investigated. Indeed, prior injection of RSV virtually completely attenuated the effects of C5a on vascular permeability, neutrophil migration, release of interleukin 1 beta, tumor necrosis factor alpha, interleukin 6, and the chemokine MIP-1 alpha. Taken together, these data demonstrate strong anti-inflammatory activity of RSV in vitro and in vivo and highlight SphK1 as a potential target of this remarkable phytoalexin. These data could have tremendous implications for the clinical use of RSV in inflammatory pathologies.-Issuree, P. D. A., Pushparaj, P. N., Pervaiz, S., Melendez, A. J. Resveratrol attenuates C5a-induced inflammatory responses in vitro and in vivo by inhibiting phospholipase D and sphingosine kinase activities. FASEB J. 23, 2412-2424 (2009)
引用
收藏
页码:2412 / 2424
页数:13
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