Abstract
The atherogenic cytokine IL-6 (interleukin-6) induces pro-inflammatory gene expression in VECs (vascular endothelial cells) by activating the JAK (Janus kinase)/STAT3 (signal transducer and activator of transcription 3) signalling pathway, which is normally down-regulated by the STAT3-dependent induction of the E3 ubiquitin ligase component SOCS3 (suppressor of cytokine signalling 3). Novel treatments based on the regulation of SOCS3 protein levels could therefore have value in the treatment of diseases with an inflammatory component, such as 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 with the action of traditional JAK/STAT3 inhibitors and the polyphenol resveratrol, which effectively suppress SOCS3 gene expression. Both naringenin and flavone also effectively suppressed IL-6-stimulated phosphorylation of STAT3 (Tyr705) which led to suppression of IL-6-induction of the atherogenic STAT3 target gene MCP1 (monocyte chemotactic protein-1), 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 cAMP-dependent, but not JAK-dependent, SOCS3 induction in VECs. Indeed, the ability of flavanoids to induce SOCS3 expression requires activation of the ERK (extracellular-signal-regulated kinase)-dependent transcription factor SP3, and not STAT3. In the present paper 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.
Highlights
Unchecked chronic inflammation is thought to be responsible for many cancers and deadly cardiovascular diseases, including atherosclerosis
As a first step to identifying potential sites for future pharmaceutical intervention to treat cardiovascular disease, we sought to investigate the molecular basis underlying the ability of naringenin to induce SOCS3 gene activity in human umbilical vein endothelial cell (HUVEC), a cell c The Authors Journal compilation c 2013 Biochemical Society model that is used routinely to study vascular endothelial cell function and pathology
Flavone, which represents the de-hydroxylated core-structure of naringenin, was found to be a much more effective inhibitor of signal transducer and activator of transcription 3 (STAT3) Tyr705 phosphorylation than naringenin, yet induced SOCS3 promoter activity to similar level as naringenin (Table 1). To examine these effects further we investigated the ability of 100 μM flavone and 100 μM resveratrol to induce the expression of SOCS3 protein in HUVECs (Figure 3a)
Summary
Unchecked chronic inflammation is thought to be responsible for many cancers and deadly cardiovascular diseases, including atherosclerosis. We found that 10 μM compound C effectively inhibited flavone-induced SOCS3 expression, but not inhibition of IL-6-promoted STAT3 activation in HUVECs (Figure 4a).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
