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.
Highlights
Mesenchymal stem cells (MSCs) are multipotent cells that can be isolated from several human tissues and expanded ex vivo for clinical use [1,2]
Because MSCs are more sensitive to radiation, we used in vitro MSCs to explore the role of Sirtuin 1 (Sirt1) in radiation-induced inflammation; we provided a theoretical basis for developing a radioprotective drug that targets Sirt1
Compared with the resveratrol group, both RNAi of Sirt1 and treatment with NAM, a Sirt1 inhibitor, suppressed resveratrol-mediated anti-inflammation, indicating that resveratrol inhibits IL-1β expression induced by radiation in a Sirt1-dependent manner
Summary
Mesenchymal stem cells (MSCs) are multipotent cells that can be isolated from several human tissues and expanded ex vivo for clinical use [1,2]. MSCs show significant potential for clinical utility due to their convenient isolation and culture conditions, low immunogenicity, regenerative and differentiation abilities, and potent immunosuppressive effects [3]. Because of these properties, an increasing number of studies suggest that the role of MSCs needs to be explored in the clinical treatment of severe radiation injuries such as radiation-induced lung injury and post-irradiation salivary gland damage [4,5,6]. Sirt can interact with the p65 subunit of NF-κb and inhibit transcription by deacetylating p65 at Lys310 and suppressing the inflammatory factor [10,11] This interaction indicates that the anti-inflammatory and cell-protective effects of Sirt may prove useful in treating radiation injury
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