The protective effect of doxofylline against lipopolysaccharides (LPS)-induced activation of NLRP3 inflammasome is mediated by SIRT1 in human pulmonary bronchial epithelial cells

Lung diseases are common health problems in many countries. The dysfunction of bronchial epithelial cells is important for the development of lung diseases. Recent progress reveals that inflammasome is the fundamental mechanism of epithelial activation. Here, we report the protective effect of doxofylline, a theophylline derivative agent, on lipopolysaccharides (LPS)-induced inflammatory response in bronchial epithelial cells. The presence of doxofylline reduces LPS-induced production of NO and PGE₂. Doxofylline also inhibits LPS-induced production of mitochondrial ROS. Mechanistically, we show that doxofylline suppresses the expression of NOX4 induced by LPS. Doxofylline inhibits LPS-induced NLRP3-TXNIP inflammasome activation as revealed by its inhibitive effect on NLRP3, Caspase 1 (P10 unit), and TXNIP induction as well as weakened induction of IL-1β and IL-18. Furthermore, we show that doxofylline ameliorates LPS-induced Sirtuin 1 (SIRT1) reduction. The silencing of SIRT1 abolishes the inhibitory effect of doxofylline on NLRP3 inflammasome activation. Collectively, our study demonstrates that doxofylline mitigates epithelial inflammation via amelioration of multiple cellular pathways, including NLRP3-TXNIP inflammasome activation.