15-deoxy-Delta(12,14)-prostaglandin J(2) inhibits fibrogenic response in human hepatoma cells.

Abstract

Liver fibrosis can be induced by environmental chemicals or toxicants, and finally stimulates fibrogenic cytokines expression, such as transforming growth factor-beta (TGF-beta) and its downstream mediator connective tissue growth factor (CTGF). 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) is a metabolite of arachidonic acid, can act as a peroxisome proliferator-activated receptor gamma (PPARgamma) 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-beta. 15d-PGJ(2) significantly inhibited TGF-beta-induced CTGF protein and mRNA expressions, and promoter activity in hepatoma cells. 15d-PGJ(2) suppressed TGF-beta-induced Smad2 phosphorylation, however enhancing the phosphorylation of ERK, c-Jun N-terminal kinase (JNK), and p38 in TGF-beta-treated Hep3B cells. Other PPAR ligands like the PPARgamma agonist, troglitazone; the PPARalpha agonist, Wy-14643, and bezafibrate were also able to inhibit TGF-beta-induced CTGF. The results suggest that 15d-PGJ(2) inhibits TGF-beta-induced CTGF expression by inhibiting the phosphorylation of Smad2, which is independent of PPAR, and 15d-PGJ(2) might also act through a PPAR-dependent mechanism in human hepatoma cells. 15d-PGJ(2) might have a beneficent effect on prevention of liver fibrosis induced by environmental toxicants.

• Authors: Fat-Moon Suk, Chien-Ho Chen, Shyr-Yi Lin, Ching-Ju Cheng, Shish-Jung Yen, Ling-Fang Hung, Der-Zen Liu, Yu-Chih Liang
• Journal: Toxicology letters (Toxicol Lett) Vol. 187 Issue 1 Pg. 22-7 (May 22 2009) ISSN: 0378-4274 [Print] Netherlands
• PMID: 19429239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 15-deoxy-delta(12,14)-prostaglandin J2
• Immunologic Factors
• RNA, Messenger
• SMAD2 protein, human
• Smad2 Protein
• Transforming Growth Factor beta
• Connective Tissue Growth Factor
• Prostaglandin D2

Topics

• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Connective Tissue Growth Factor (drug effects, genetics, metabolism)
• Fibrosis (genetics, metabolism, prevention & control)
• Gene Expression (drug effects)
• Hepatic Stellate Cells (drug effects, metabolism, pathology)
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Immunologic Factors (pharmacology)
• Liver Cirrhosis (prevention & control)
• Phosphorylation (drug effects)
• Prostaglandin D2 (analogs & derivatives, pharmacology)
• RNA, Messenger (metabolism)
• Smad2 Protein (metabolism)
• Transforming Growth Factor beta (pharmacology)
• Up-Regulation (drug effects)