Cytokines suppress adipogenesis and PPAR-function through the TAK1/TAB1/NIK cascade (Retracted Article)
Cytokines suppress adipogenesis and PPAR-function through the TAK1/TAB1/NIK cascade (Retracted Article)
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DOI：
10.1038/ncb942
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发表时间：
2003-03-01
影响因子：
21.3
通讯作者：
Kato, S
中科院分区：
文献类型：
--
作者：
Suzawa, M;Takada, I;Kato, S
骨髓中的多能间充质干细胞分化为脂肪细胞、成骨细胞和其他细胞（1，2）。干细胞的平衡分化对于骨髓的形成和维持至关重要;然而，控制这种平衡的机制在很大程度上仍然未知。细胞因子如白细胞介素-1（IL-1）和肿瘤坏死因子-α（TNF-α）抑制脂肪生成（3，4），而配体诱导的转录因子过氧化物酶体增殖物激活受体-γ（5）（PPAR-gamma）是脂肪生成的关键诱导剂。因此，细胞因子和PPAR-gamma介导的信号之间的调节偶联可能发生在脂肪形成过程中。在这里，我们发现配体诱导的PPAR-γ的反式激活功能被IL-1和TNF-α抑制，并且这种抑制是通过由TAK 1/TAB 1/NF-κ B诱导激酶（NIK）级联激活的NF-κ B介导的（6-9），这是一种与IL-1和TNF-α信号传导相关的下游级联。与通过A/B结构域磷酸化的丝裂原活化蛋白激酶诱导的生长因子信号传导抑制PPAR-γ反式激活功能不同（10），NF-κ B通过与PPAR-γ及其AF-1特异性共激活因子PGC-2形成复合物来阻断PPAR-γ与DNA的结合。我们的研究结果表明，IL-1和TNF-α在骨髓中的表达可能会改变多能间充质干细胞的命运，通过TAK 1/TAB 1/NIK级联激活的NF-κ B抑制PPAR-gamma功能，引导细胞向成骨细胞而不是脂肪细胞分化。
Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes, osteoblasts and other cells(1,2). Balanced cytodifferentiation of stem cells is essential for the formation and maintenance of bone marrow; however, the mechanisms that control this balance remain largely unknown. Whereas cytokines such as interleukin-1 (IL-1) and tumour-necrosis factor-alpha (TNF-alpha) inhibit adipogenesis(3,4), the ligand-induced transcription factor peroxisome proliferator-activated receptor-gamma(5) (PPAR-gamma), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF-kappaB-inducing kinase (NIK) cascade(6-9), a downstream cascade associated with IL-1 and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain(10), NF-kappaB blocks PPAR-gamma binding to DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.