TNF-alpha regulates mouse fetal hepatic maturation induced by oncostatin M and extracellular matrices

Fetal hepatic maturation consists of multisteps and is regulated by several cytokines and cell-cell or cell-matrices interactions. In the mid-to-late fetal stage, hepatocytes have few metabolic functions associated with adult liver homeostasis. Cultured fetal hepatocytes acquire the expression of several mature liver-specific genes through stimulation with hepatic maturation factor oncostatin M (OSM) and matrigel. Tumor necrosis factor-alpha (TNFalpha) regulates fetal hepatic maturation stimulated by OSM and matrigel. TNFalpha suppressed expression of mature liver-specific genes such as tyrosine aminotransferase and apolipoproteins. In addition, the expression of hematopoietic cytokines and cyclin A2, repressed by OSM and matrigel, is induced by TNFalpha in the fetal hepatic cultures coincident with cell division. TNFalpha inhibited the induction of hepatocyte nuclear factor 4alpha induced by OSM and matrigel, suggesting that down-regulation of hepatocyte nuclear factor 4alpha expression is involved in the mechanism of suppression of hepatic maturation by TNFalpha. Interestingly, TNFalpha is expressed in the prenatal and postnatal liver but not in adult liver, whereas TNFR1, a TNFalpha receptor, is expressed in both fetal and adult livers. In conclusion, TNFalpha is a suppressive factor of hepatic maturation. The balance between hepatic maturation factor (OSM and extracellular matrices) and TNFalpha is important for liver development.