Abstract
Resveratrol (RSV) and nicotinamide (NAM) have garnered considerable attention due to their anti-inflammatory and anti-aging properties. NAM is a transient inhibitor of class III histone deacetylase SIRTs (silent mating type information regulation 2 homologs) and SIRT1 is an inhibitor of poly-ADP-ribose polymerase-1 (PARP1). The debate on the relationship between RSV and SIRT1 has precluded the use of RSV as a therapeutic drug. Recent work demonstrated that RSV facilitates tyrosyl-tRNA synthetase (TyrRS)-dependent activation of PARP1. Moreover, treatment with NAM is sufficient to facilitate the nuclear localization of TyrRS that activates PARP1. RSV and NAM have emerged as potent agonists of PARP1 through inhibition of SIRT1. In this study, we evaluated the effects of RSV and NAM on pro-inflammatory macrophages. Our results demonstrate that treatment with either RSV or NAM attenuates the expression of pro-inflammatory markers. Strikingly, the combination of RSV with NAM, exerts additive effects on PARP1 activation. Consistently, treatment with PARP1 inhibitor antagonized the anti-inflammatory effect of both RSV and NAM. For the first time, we report the ability of NAM to augment PARP1 activation, induced by RSV, and its associated anti-inflammatory effects mediated through the induction of BCL6 with the concomitant down regulation of COX-2.
Highlights
Inflammation is commonly treated with non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibodies, and biological agents
RSV facilitates the activation of poly-ADP-ribose polymerase-1 (PARP1) and accumulation of poly(ADP-ribose) that would lead to ADP-ribose-driven modulation of PDE and subsequent upregulation of cAMP and associated Ca2+ signaling[21,22]
We report the ability of NAM to activate PARP1 and its associated anti-inflammatory effects mediated through the induction of B-cell lymphoma-6 protein (BCL6) with the concomitant down regulation of COX-2
Summary
Inflammation is commonly treated with non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antibodies, and biological agents. RSV facilitates the activation of PARP1 and accumulation of poly(ADP-ribose) that would lead to ADP-ribose-driven modulation of PDE and subsequent upregulation of cAMP and associated Ca2+ signaling[21,22] These two studies[21,22] suggest that PARP1 and PDE4 act in tandem to exert the metabolic benefits of resveratrol. Significant effort has been dedicated to modulate the phenotypic adaptation of macrophages as a therapeutic target for pathologies[62,63,64,65] To this end, we demonstrate that synergistic activation of PARP1 mediated by RSV and NAM can be exploited as a strategy to tune inflammatory response
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