Fibrinogen-like
protein 2 (FGL2)/fibroleukin plays a pivotal role in the pathogenesis of experimental and human fulminant and chronic viral
hepatitis. To define the
transcription factor(s) and upstream signal transduction pathways involved in the transcription of human FGL2 (hFGL2) in response to
hepatitis B (HB) virus, hepatitis B core (HBc), hepatitis B virus S
protein (HBs), or
hepatitis B virus X protein (HBx)
protein, expression plasmids were cotransfected with an hFGL2 promoter
luciferase reporter construct into Chinese hamster ovary and HepG2 cells, respectively. HBc and HBx
proteins, but not HBs
protein, enhanced hFGL2 transcription in both cell lines. A strong regulatory region from -712 to -568 (relative to the transcriptional starting site) was shown to be responsible for hFGL2 gene transcription in response to both HBc and HBx
proteins. c-Ets-2 was shown to be translocated to the nucleus in association with hFGL2 expression in response to both HBc and HBx
proteins.
Short hairpin RNA (
shRNA) interference of c-Ets-2 expression inhibited hFGL2 gene transcription by 64.8 and 60.0% in response to HBc and HBx, respectively.
c-Ets-2 protein was highly expressed in peripheral blood mononuclear cells from patients with severe
chronic hepatitis B (CHB) in contrast to patients with mild CHB. Increased phosphorylation of ERK and JNK was detected in peripheral blood mononuclear cells from patients with severe CHB. ERK inhibitor
PD098059 or ERK
shRNA abolished the nuclear c-Ets-2
DNA binding activity and hFGL2 induction in response to HBc, whereas JNK inhibitor
SP600125 or JNK
shRNA abolished the nuclear c-Ets-2
DNA binding activity and hFGL2 induction in response to HBx. In conclusion, HBc and HBx
proteins enhance transcription of hFGL2 through c-Ets-2 dependent on MAPK signal pathways.