15-Deoxy-Δ12,14-prostaglandin J2 inhibits fibrogenic response in human hepatoma cells

Liver fibrosis can be induced by environmental chemicals or toxicants, and finally stimulates fibrogenic cytokines expression, such as transforming growth factor-β (TGF-β) and its downstream mediator connective tissue growth factor (CTGF). 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a metabolite of arachidonic acid, can act as a peroxisome proliferator-activated receptor γ (PPARγ) ligand, and function as either anti-inflammatory or inflammatory agents in different cell types. In this study, CTGF was detected in three human hepatoma cell lines, Hep3B, HepG2, and Huh-7, and it was up-regulated by TGF-β. 15d-PGJ2 significantly inhibited TGF-β-induced CTGF protein and mRNA expressions, and promoter activity in hepatoma cells. 15d-PGJ2 suppressed TGF-β-induced Smad2 phosphorylation, however enhancing the phosphorylation of ERK, c-Jun N-terminal kinase (JNK), and p38 in TGF-β-treated Hep3B cells. Other PPAR ligands like the PPARγ agonist, troglitazone; the PPARα agonist, Wy-14643, and bezafibrate were also able to inhibit TGF-β-induced CTGF. The results suggest that 15d-PGJ2 inhibits TGF-β-induced CTGF expression by inhibiting the phosphorylation of Smad2, which is independent of PPAR, and 15d-PGJ2 might also act through a PPAR-dependent mechanism in human hepatoma cells. 15d-PGJ2 might have a beneficent effect on prevention of liver fibrosis induced by environmental toxicants.