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

Priya D. A. Issuree^*, Peter N. Pushparaj^*,, Shazib Pervaiz^*,,,||,1,2 and Alirio J. Melendez^*,,,1,2

^* Department of Physiology, Yong Loo Lin School of Medicine,

NUS Graduate School for Integrative Sciences and Engineering, and

Duke-NUS Graduate Medical School, National University of Singapore, Singapore;

Medicine-Immunology, Infection, and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK; and

^|| Singapore-Massachusetts Institute of Technology Alliance, Singapore

² Correspondence: S.P., Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597. E-mail: phssp{at}nus.edu.sg; or A.J.M., Division of Immunology, Infection, and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, UK. E-mail: a.melendez-romero{at}clinmed.gla.ac.uk

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 20µM) 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 1β, tumor necrosis factor , interleukin 6, and the chemokine MIP-1. 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.

Key Words: infl131ammation • neutrophil migration • oxidative burst • chemotaxis • ERK1/2 • anaphylatoxin