Suk Fat-Moon, Chen Chien-Ho, Lin Shyr-Yi, Cheng Ching-Ju, Yen Shish-Jung, Hung Ling-Fang, Liu Der-Zen, Liang Yu-Chih
Department of Internal Medicine, Taipei Medical University Hospital and Wan-Fang Hospital, Taipei, Taiwan.
Toxicol Lett. 2009 May 22;187(1):22-7. doi: 10.1016/j.toxlet.2009.01.019. Epub 2009 Jan 23.
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.
肝纤维化可由环境化学物质或毒物诱导产生，最终刺激促纤维化细胞因子的表达，如转化生长因子-β（TGF-β）及其下游介质结缔组织生长因子（CTGF）。15-脱氧-Δ¹²,¹⁴-前列腺素J₂（15d-PGJ₂）是花生四烯酸的一种代谢产物，可作为过氧化物酶体增殖物激活受体γ（PPARγ）的配体，并在不同细胞类型中发挥抗炎或促炎作用。在本研究中，在三种人肝癌细胞系Hep3B、HepG2和Huh-7中检测到CTGF，且其表达受TGF-β上调。15d-PGJ₂显著抑制TGF-β诱导的肝癌细胞中CTGF蛋白和mRNA表达以及启动子活性。15d-PGJ₂抑制TGF-β诱导的Smad2磷酸化，但增强TGF-β处理的Hep3B细胞中ERK、c-Jun氨基末端激酶（JNK）和p38的磷酸化。其他PPAR配体，如PPARγ激动剂曲格列酮、PPARα激动剂Wy-14643和苯扎贝特，也能够抑制TGF-β诱导的CTGF。结果表明，15d-PGJ₂通过抑制Smad2磷酸化来抑制TGF-β诱导的CTGF表达，这一作用独立于PPAR，并且15d-PGJ₂在人肝癌细胞中可能也通过PPAR依赖性机制发挥作用。15d-PGJ₂可能对预防环境毒物诱导的肝纤维化具有有益作用。
