Activator protein‑1 is a novel regulator of mesencephalic astrocyte‑derived neurotrophic factor transcription

Mesencephalic astrocyte‑derived neurotrophic factor (MANF) is an endoplasmic reticulum stress‑inducible protein, which has been suggested to be upregulated in inflammatory diseases; however, how inflammation regulates its transcription remains unclear. Activator protein‑1 (AP‑1), which is a transcription factor complex composed of c‑Fos and c‑Jun, is activated during the inflammatory process. The present study aimed to investigate whether the AP‑1 complex regulates MANF transcription. The results of a luciferase reporter assay revealed that one of three putative AP‑1 binding sites in the MANF promoter region is essential for enhancement of MANF transcription. Mechanistically, AP‑1 was revealed to directly bind to the promoter region of the MANF gene by chromatin immunoprecipitation assay. Furthermore, MANF was strongly expressed in the liver tissues of patients with hepatitis B virus (HBV) infection, compared with in normal liver tissues from patients with hepatic hemangioma. Furthermore, c‑Fos and c‑Jun were also upregulated in the nuclei of hepatocytes from patients with HBV infection. In mice treated with carbon tetrachloride, the expression patterns of MANF, c‑Fos and c‑Jun were similar to those in patients with HBV. These results suggested that the AP‑1 complex may be a novel regulator of MANF transcription, which may be involved in liver inflammation and fibrosis.