Phosphorylated STAT3 suppresses microRNA‐19b/1281 to aggravate lung injury in mice with type 2 diabetes mellitus‐associated pulmonary tuberculosis
Xianhua Wang, Yuefu Lin, Ying Liang, Yang Ye, Dong Wang, Aer Tai, Shuimiao Wu, Jian Pan
Abstract
Type 2 diabetes mellitus (T2DM) is a risk factor for pulmonary tuberculosis (PTB) and increased mortality. This work focused on the functions of phosphorylated STAT3 in lung injury in mouse with T2DM-associated PTB and the molecules involved. A mouse model with T2DM-PTB was induced by administrations of streptozotocin, nicotinamide and mycobacterium tuberculosis (Mtb). A pSTAT3-specific inhibitor AG-490 was given into mice and then the lung injury in mice was observed. The molecules involved in AG-490-mediated events were screened out. Altered expression of miR-19b, miR-1281 and NFAT5 was introduced to identify their involvements and roles in lung injury and PTB severity in the mouse model. Consequently, pSTAT3 expression in mice with T2DM-associated PTB was increased. Down-regulation of pSTAT3 by AG-490 prolonged the lifetime of mice and improved the histopathologic conditions, and inhibited the fibrosis, inflammation, Mtb content and number of apoptotic epithelial cells in mouse lung tissues. pSTAT3 transcriptionally suppressed miR-19b/1281 expression to up-regulate NFAT5. Inhibition of miR-19b/1281 or up-regulation of NFAT5 blocked the protective roles of AG-490 in mouse lung tissues. To conclude, this study evidenced that pSTAT3 promotes NFAT5 expression by suppressing miR-19b/1281 transcription, leading to lung injury aggravation and severity in mice with T2DM-associated PTB.