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.