Chae Gi-Nam, Kwak Sahng-June
Department of Biochemistry, College of Medicine, Dankook University, San 29 Anseo-dong, Cheonan 330-714, Korea.
Exp Mol Med. 2003 Oct 31;35(5):431-7. doi: 10.1038/emm.2003.56.
TNF-alpha, a trimeric cytokine, was known to inhibit differention of preadipocytes to adipocytes. In the present study, we investigated signal mediators working downstream of TNF-alpha using murine 3T3-L1 cells. TNF-alpha induced activation of both c-jun NH(2)-terminal kinase (JNK) and nuclear transcription factor-kappaB (NF-kappaB) in 3T3-L1 cells. Blockage of these two mediators activities by specific inhibitors, SP600125 and Ad-IkappaBalpha-SR restored adipogenesis differentiation suggesting their involvement in the inhibited differentiation of 3T3-L1 cells by TNF-alpha. Consistent with previous studies, peroxisome proliferator-activated receptor gamma (PPARgamma) a key transcriptional regulator was remarkably reduced by TNF-alpha treatment. Compared with adipogenesis, however, SP600125, a chemical JNK inhibitor hardly relieved TNF-alpha effect on PPARgamma expression whereas S32A/S36A mutant of IkappaBalpha considerably recovered PPARgamma expression, indicating that two signal mediators exploit separable main routes to achieve reduced adipogenesis. These results suggest that inhibition of 3T3-L1 cells differentiation by TNF-alpha is partly implemented through NF-kappaB and one of its downstream effectors be PPARgamma.
肿瘤坏死因子-α（TNF-α）是一种三聚体细胞因子，已知其可抑制前脂肪细胞向脂肪细胞的分化。在本研究中，我们使用小鼠3T3-L1细胞研究了在TNF-α下游发挥作用的信号介质。TNF-α可诱导3T3-L1细胞中的c-jun氨基末端激酶（JNK）和核转录因子-κB（NF-κB）活化。用特异性抑制剂SP600125和Ad-IκBα-SR阻断这两种介质的活性可恢复脂肪生成分化，表明它们参与了TNF-α对3T3-L1细胞分化的抑制作用。与先前的研究一致，过氧化物酶体增殖物激活受体γ（PPARγ）这一关键转录调节因子在TNF-α处理后显著降低。然而，与脂肪生成相比，化学JNK抑制剂SP600125几乎不能缓解TNF-α对PPARγ表达的影响，而IκBα的S32A/S36A突变体则显著恢复了PPARγ的表达，表明两种信号介质利用可分离的主要途径来实现脂肪生成减少。这些结果表明，TNF-α对3T3-L1细胞分化的抑制作用部分是通过NF-κB实现的，其下游效应器之一是PPARγ。
