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. FASEB J. 33, 12554–12564 (2019). http://www.fasebj.org
Background Histone deacetylase (HDAC) inhibition was reported to ameliorate lung fibrosis in animal models. However, little is known about the underlying mechanism of HDAC7 in the regulation of CTGF production in lung fibroblasts. Methods The role of HDAC7 in CTGF production caused by ET-1 stimulation in WI-38 cells (human lung fibroblast) was examined. We also evaluated the expression of HDAC7 in the lung of ovalbumin-induced airway fibrosis model. Statistical data were shown as mean ± standard error. Results ET-1-stimulated CTGF and α-SMA expression was attenuated by small interfering (si)RNA interference of HDAC7. ET-1 promoted HDAC7 translocation from the cytosol to nucleus. ET-1-stimulated CTGF expression was reduced by the transfection of p300 siRNA. ET-1 induced an increase in p300 activity. Furthermore, the acetylation of c-Jun was time-dependently induced by ET-1 stimulation, which was reduced by transfection of either HDAC7 or p300 siRNA. Both transfection of HDAC7 and p300 siRNA suppressed the ET-1-increased activity of AP-1-luciferase. Moreover, the presence of HDAC7 was required for ET-1-stimulated formation of HDAC7, p300, and AP-1 complex and recruitment to the CTGF promoter region. In an ovalbumin-induced airway fibrosis model, the protein level of HDAC7 was increased in the lung tissue, and the distribution of HDAC7 was colocalized with α-SMA-positive cells in the subepithelial layer of the airway. Conclusions ET-1 activates HDAC7 to initiate AP-1 transcriptional activity by recruiting p300 and eventually promotes the production of CTGF. HDAC7 might play a vital role in airway fibrosis and have the potential to be developed as a therapeutic target.
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