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

Abstract

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.