Resveratrol Inhibits Ionising Irradiation-Induced Inflammation in MSCs by Activating SIRT1 and Limiting NLRP-3 Inflammasome Activation

Abstract

IL-1β, a pro-inflammatory cytokine, has been shown to contribute to radiation injury. Sirt1, an NAD+-dependent class III protein deacetylase, plays an important role in the regulation of the proinflammatory cytokines involved in inflammation-associated diseases. The relationship between Sirt1 and IL-1β, however, has remained elusive. The present study was designed to explore the potential effect of Sirt1 on IL-1β expression induced by radiation and to provide a new target for the development of radiation protection drugs. Our results showed that radiation significantly increased IL-1β mRNA and protein expression and that pretreatment with resveratrol, a Sirt1 activator, inhibited the radiation-induced IL-1β expression in a concentration-dependent manner, whereas the knockdown or inhibition of Sirt1 by nicotinamide significantly enhanced radiation-induced IL-1β expression. This effect can likely be attributed to Sirt1-mediated inhibition of NLRP-3 inflammasome activation because Sirt1 inhibits the transactivation potential of NF-κb by deacetylation, which then suppresses NLRP3 transcription. Taken together, the results demonstrate that Sirt1 exerts anti-inflammatory effects by regulating NLRP3 expression partially through the NF-κb pathway in mesenchymal stem cells. More importantly, our findings suggest that resveratrol is an effective agent in protecting against radiation injury, and we provide a theoretical basis for developing a drug to protect against radiation injury by targeting Sirt1.

Role of Interleukin-1 in Radiation-Induced Cardiomyopathy

“…IL-1β is synthesized as an inactive precursor (pro-IL-1β) that is cleaved by caspase-1 following formation of the inflammasome consequent to tissue injury, as following XRT (11)(12)(13)27,28). The activation of the inflammasome pathway may be due to the production of reactive oxygen species after exposure to ionizing radiation or to the production or release of damage-associated molecular patterns by irradiated cells (27)(28)(29)(30)). Activation of the inflammasome then leads to IL-1β processing and release, and inflammatory cell death, leading to amplification of the inflammatory response and injury (31).…”

Inhibition of STAT3 acetylation is associated with attenuated renal fibrosis in the obstructed kidney

“…As a SIRT1 activator [42,43] , resveratrol was used to identify whether acetylated STAT3 is involved in the activation of STAT3 signaling. The basal STAT3 acetylation on Lys685 was decreased by resveratrol, resulting in negation of Ang II-induced upregulation www.chinaphar.com Ni J et al Acta Pharmacologica Sinica npg of STAT3 Try705 phosphorylation and the downstream profibrotic genes.…”

“…Resveratrol, an activator of SIRT1 [42,43] , reduced the basal STAT3 acetylation on Lys685 ( Figure 3A). Resveratrol pretreatment of tubular epithelial cells prevented Ang II-induced upregulation of STAT3 phosphorylation on Tyr705 ( Figure 3A).…”

“…One of the best characterized deacetylases is sirtuin 1 (SIRT1), a member of nicotinamide adenine dinucleotide (NAD + )-dependent class III protein deacetylases, which can be inhibited by nicotinamide [35,36] . SIRT1, which mediates the deacetylation of STAT3 Lys685 site [37][38][39][40][41] , can be activated by resveratrol (trans-3,4',5-trihydroxystilbene) [42,43] , a natural polyphenol with renal protective effects that depend on deacetylation of Smad3 [44] , p53 [45] , and NF-κB p65 [46] . However, the role of STAT3 acetylation in the antifibrotic activity of resveratrol has yet to be clarified.…”

Plant Extracts and Plant-Derived Compounds: Promising Players in Countermeasure Strategy Against Radiological Exposure: A Review

“…Agents that can be radioprotective must counter some or all the damaging effects of radiological exposure in the cell including those mentioned above. Radiation-induced inflammation, an important side effect that contributes to normal tissue injury, has been reported in many species (Linard et al, 2004;Fliedner et al, 2005;Kong et al, 2005;Fleckenstein et al, 2007;Haston et al, 2007;Rodemann and Blaese, 2007;Hill et al, 2011;Multhoff and Radons, 2012;Rastogi et al, 2012;Cho et al, 2013;Fu et al, 2013;Jiang et al, 2013;McCurdy et al, 2013;Moore et al, 2013;Mukherjee et al, 2014). The initial phase of radiationinduced injury is marked by the increase in the synthesis of pro-inflammatory cytokines such as transforming growth factor-beta1 (TGF-β1), tumor necrosis factor-alpha (TNF-α) and several other members of interleukin (IL) family (Linard et al, 2004;Fliedner et al, 2005;Kong et al, 2005;Mehta, 2005;Fleckenstein et al, 2007;Haston et al, 2007;Rodemann and Blaese 2007;Jindal et al, 2009;Hei et al, 2011;Janko et al, 2012;Monceau et al, 2013).…”