Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL6- activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells

Wiejak, J., Dunlop, J. , Mackay, S. P. and Yarwood, S. J. (2013) Flavanoids induce expression of the suppressor of cytokine signalling 3 (SOCS3) gene and suppress IL6- activated signal transducer and activator of transcription 3 (STAT3) activation in vascular endothelial cells. Biochemical Journal, 454(2), pp. 283-293. (doi: 10.1042/BJ20130481)

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Publisher's URL: http://dx.doi.org/10.1042/BJ20130481

Abstract

The atherogenic cytokine interleukin-6 (IL6) induces pro-inflammatory gene expression in vascular endothelial cells (VECs) by activating the JAK/STAT3 signalling pathway, which is normally down-regulated by the STAT3-dependent induction of the E3 ubiquitin ligase component, SOCS3. Novel treatments based on the regulation of SOCS3 protein levels could therefore have value in the treatment of diseases with an inflammatory component, like atherosclerosis. To this end we carried out a screen of 1031 existing medicinal compounds to identify inducers of SOCS3 gene expression and identified the flavanoids, naringenin and flavone, as effective inducers of SOCS3 protein, mRNA and promoter activity. This was in contrast to the action of traditional JAK/STAT3 inhibitors, and the polyphenol resveratrol, which effectively suppress SOCS3 gene expression. Both naringenin and flavone also effectively suppressed IL6-stimulated phosphorylation of STAT3 (Tyr 705) which led to suppression of IL6-induction of the atherogenic, STAT3 target gene MCP1, suggesting that their ability to induce SOCS3 gene expression is STAT3 independent. Supporting this idea was the observation that the general kinase inhibitor, compound C, inhibits flavone- and cyclic AMP-dependent, but not JAK-dependent, SOCS3 induction in VECs. Indeed, the ability of flavanoids to induce SOCS3 expression requires activation of the ERK-dependent transcription factor, SP3, and not STAT3. We therefore describe novel molecular actions of flavanoids, which control SOCS3 gene induction and suppression of STAT3 signalling in VECs. These mechanisms could potentially be exploited to develop novel anti-atherogenic therapies.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Yarwood, Dr Stephen and Dunlop, Mrs Julia and Wiejak, Dr Jolanta
Authors: Wiejak, J., Dunlop, J., Mackay, S. P., and Yarwood, S. J.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Biochemical Journal
Publisher:Portland Press Ltd.
ISSN:0264-6021
ISSN (Online):1470-8728
Copyright Holders:Copyright © 2013 The Authors
First Published:First published in Biochemical Journal 454(2):283-293
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
528251The Role of EPAC1-regulated Protein Kinase C Isoforms in Mediating C/EBPdelta -dependent, Anti-inflammatory Actions of Cyclic AMP in Vascular Endothelial CellsStephen YarwoodBritish Heart Foundation (BHF)PG/10/026/28303RI MOLECULAR CELL & SYSTEMS BIOLOGY