Abstract
Mycobacterium tuberculosis (M.tb) infection in lung causes pulmonary fibrosis, which leads to the irreversible reduction of pulmonary function. Fibrotic protein connective tissue growth factor (CTGF) expression has been confirmed to play a crucial role in lung fibrosis. However, the underlying signal pathway and effect of M.tb on CTGF expression in human lung fibroblasts are unclear. Our results revaled that M.tb caused time- and concentration-dependent increases in CTGF expression in human lung fibroblasts. A mechanistic investigation revealed that M.tb induced CTGF expression through TLR2 but not TLR4. The promoter activity assay indicated that M.tb-induced CTGF activity was mainly controlled by the promoter region at -747 to -184 bp, which contained signal transducer and activator of transcription 3 and activator protein 1 (AP-1) binding sites. Moreover, curcumin (AP-1 inhibitor) restrained M.tb-induced CTGF expression. M.tb also induced increases in AP-1 luciferase activity and DNA binding activity of c-Jun and c-Fos on the CTGF promoter. Furthermore, the knockdown of c-Jun by small interfering RNA attenuated M.tb-induced CTGF expression and AP-1 luciferase activity. A JNK inhibitor (SP600125) and a JNK dominant-negative mutant suppressed M.tb-induced CTGF expression. We also discovered that M.tb could induce the phosphorylation of JNK and c-Jun. Furthermore, SP600125 inhibited M.tb-induced c-Jun phosphorylation and AP-1- luciferase activity. M.tb-induced fibronectin expression was inhibited by anti-CTGF antibody. These results demonstrate that M.tb is activated through TLR2 to induce JNK activation, further increasing the DNA binding activity of c-Jun and c-Fos and finally inducing CTGF expression and extracellular matrix production.-Lee, H.-S., Hua, H.-S., Wang, C.-H., Yu, M.-C., Chen, B.-C., Lin, C.-H. Mycobacterium tuberculosis induces connective tissue growth factor expression through the TLR2-JNK-AP-1 pathway in human lung fibroblasts.