Yang Se-Ran, Wright Jessica, Bauter Mark, Seweryniak Kathryn, Kode Aruna, Rahman Irfan
Department of Environmental Medicine, Division of Lung Biology and Disease, University of Rochester Medical Center, MRBX 3.11106, 601 Elmwood Ave., Box 850, Rochester, NY 14642, USA.
Am J Physiol Lung Cell Mol Physiol. 2007 Feb;292(2):L567-76. doi: 10.1152/ajplung.00308.2006. Epub 2006 Oct 13.
The silent information regulator 2 (Sir2) family of proteins (sirtuins or SIRTs), which belong to class III histone/protein deacetylases, have been implicated in calorie restriction, aging, and inflammation. We hypothesized that cigarette smoke-mediated proinflammatory cytokine release is regulated by SIRT1 by its interaction with NF-kappaB in a monocyte-macrophage cell line (MonoMac6) and in inflammatory cells of rat lungs. Cigarette smoke extract (CSE) exposure to MonoMac6 cells caused dose- and time-dependent decreases in SIRT1 activity and levels, which was concomitant to increased NF-kappaB-dependent proinflammatory mediator release. Similar decrements in SIRT1 were also observed in inflammatory cells in the lungs of rats exposed to cigarette smoke as well as with increased levels of several NF-kappaB-dependent proinflammatory mediators in bronchoalveolar lavage fluid and in lungs. Sirtinol, an inhibitor of SIRT1, augmented, whereas resveratrol, an activator of SIRT1, inhibited CSE-mediated proinflammatory cytokine release. CSE-mediated inhibition of SIRT1 was associated with increased NF-kappaB levels. Furthermore, we showed that SIRT1 interacts with the RelA/p65 subunit of NF-kappaB, which was disrupted by cigarette smoke, leading to increased acetylation RelA/p65 in MonoMac6 cells. Thus our data show that SIRT1 regulates cigarette smoke-mediated proinflammatory mediator release via NF-kappaB, implicating a role of SIRT1 in sustained inflammation and aging of the lungs.
沉默信息调节因子2（Sir2）蛋白家族（沉默调节蛋白或SIRTs）属于III类组蛋白/蛋白脱乙酰酶，与热量限制、衰老和炎症有关。我们推测，香烟烟雾介导的促炎细胞因子释放是由SIRT1通过其在单核巨噬细胞系（MonoMac6）和大鼠肺炎症细胞中与核因子κB（NF-κB）的相互作用来调节的。香烟烟雾提取物（CSE）暴露于MonoMac6细胞会导致SIRT1活性和水平呈剂量和时间依赖性降低，这与NF-κB依赖性促炎介质释放增加相伴。在暴露于香烟烟雾的大鼠肺炎症细胞中也观察到了SIRT1的类似降低，同时支气管肺泡灌洗液和肺中几种NF-κB依赖性促炎介质水平升高。SIRT1抑制剂sirtinol增强了这种作用，而SIRT1激活剂白藜芦醇则抑制了CSE介导的促炎细胞因子释放。CSE介导的对SIRT1的抑制与NF-κB水平升高有关。此外，我们表明SIRT1与NF-κB的RelA/p65亚基相互作用，这种相互作用被香烟烟雾破坏，导致MonoMac6细胞中RelA/p65乙酰化增加。因此，我们的数据表明，SIRT1通过NF-κB调节香烟烟雾介导的促炎介质释放，这意味着SIRT1在肺的持续炎症和衰老中发挥作用。
