Sirtuin 1 promotes Th2 responses and airway allergy by repressing peroxisome proliferator-activated receptor-γ activity in dendritic cells.

Sirtuins are a unique class of NAD(+)-dependent deacetylases that regulate diverse biological functions such as aging, metabolism, and stress resistance. Recently, it has been shown that sirtuins may have anti-inflammatory activities by inhibiting proinflammatory transcription factors such as NF-κB. In contrast, we report in this study that pharmacological inhibition of sirtuins dampens adaptive Th2 responses and subsequent allergic inflammation by interfering with lung dendritic cell (DC) function in a mouse model of airway allergy. Using genetic engineering, we demonstrate that sirtuin 1 represses the activity of the nuclear receptor peroxisome proliferator-activated receptor-γ in DCs, thereby favoring their maturation toward a pro-Th2 phenotype. This study reveals a previously unappreciated function of sirtuin 1 in the regulation of DC function and Th2 responses, thus shedding new light on our current knowledge on the regulation of inflammatory processes by sirtuins.

Asthmatic bronchial fibroblasts demonstrate enhanced potential to differentiate into myofibroblasts in culture.

BACKGROUND: Chronic inflammation and remodeling of the bronchial wall are basic hallmarks of asthma. It is known that mesenchymal cells in the lamina reticularis underlying the basement membrane of the thickened airway wall of asthmatics predominantly display the phenotype of myofibroblasts and express alpha-smooth muscle actin (alpha-SMA). Human bronchial fibroblasts (HBFs) transform in vitro into myofibroblasts under the influence of transforming growth factor (TGF-beta). Differences in the reactivity of fibroblasts to TGF-beta in cultures derived from healthy and asthmatic donors are elucidated here. MATERIAL/METHODS: Primary human bronchial fibroblasts (HBFs) were cultured from bronchial biopsies from non-asthmatic (n=7) and asthmatic (n=7) donors and treated with TGF-beta1 or TGF-beta2 to induce myofibroblast differentiation. Expression of alpha-smooth muscle actin (alpha-SMA) was assessed by immunocytochemistry and Western blotting. The cell size and shape parameters were measured by computer-aided methods. RESULTS: Regardless of whether TGF-beta1 or TGF-beta2 was used, asthmatic cells showed enhanced expression of the myofibroblast marker as confirmed by immunocytochemistry and immunoblotting. Analysis of the shape parameters of cells incubated in the presence of TGF-beta1 revealed that HBFs of asthmatics differ from those of non-asthmatics. CONCLUSIONS: It is concluded that asthmatic HBFs cultured in vitro display some inherent features which facilitate their differentiation into myofibroblasts. These data indicate that increased reactivity of asthmatic fibroblasts to TGF-beta may play a crucial role in asthma.