Transforming growth factor β1 rescues serum deprivation-induced apoptosis via the mitogen-activated protein kinase (MAPK) pathway in macrophages
Transforming growth factor β1 rescues serum deprivation-induced apoptosis via the mitogen-activated protein kinase (MAPK) pathway in macrophages
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DOI：
10.1074/jbc.274.16.11362
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发表时间：
1999-04-16
影响因子：
4.8
通讯作者：
Choi, ME
中科院分区：
文献类型：
--
作者：
Chin, BY;Petrache, I;Choi, ME
细胞死亡和细胞存活是正常发育和病理状态的核心组成部分。转化生长因子β(1) (TGF-β(1)) 是一种多效性细胞因子，可调节细胞生长和细胞死亡。为了更好地了解控制细胞死亡或存活的分子机制，我们通过显性抑制 TGF-β(1) 和丝裂原激活蛋白激酶 (MAPK) 信号通路来研究 TGF-β(1) 在细胞凋亡过程中的作用。通过 DNA 阶梯分析确定，小鼠巨噬细胞 (RAW 264.7) 在血清剥夺后发生细胞凋亡。然而，外源性 TGF-β(1) 的存在可阻止血清剥夺巨噬细胞的细胞凋亡。使用稳定转染的 RAW 264.7 细胞和 T beta R-II (T beta R-IIM) cDNA 的激酶缺失显性失活突变体，我们证明 TGF-beta(1) 的这种保护作用被完全消除。为了确定下游信号通路，我们检查了 TGF-β(1) 对 MAPK 通路的影响。我们发现，TGF-β(1) 在刺激后长达 4 小时内以时间依赖性方式诱导细胞外信号调节激酶 (ERK) 活性。此外，在转染显性失活突变体 MAPK (ERK2) cDNA 的 RAW 264.7 细胞中或在 MAPK 激酶 (MEK1) 抑制剂存在的情况下，在野生型 RAW 264.7 细胞中，TGF-beta(1) 不能挽救血清剥夺诱导的细胞凋亡。总而言之，我们的数据首次证明 TGF-β(1) 是培养巨噬细胞中细胞凋亡的抑制剂，并且可能通过 T beta R-II 介导的信号传导和下游细胞内 MAPK 信号传导途径充当细胞存活因子。
Cell death and cell survival are central components of normal development and pathologic states. Transforming growth factor beta(1) (TGF-beta(1)) is a pleiotropic cytokine that regulates both cell growth and cell death. To better understand the molecular mechanisms that control cell death or survival, we investigated the role of TGF-beta(1) in the apoptotic process by dominant-negative inhibition of both TGF-beta(1) and mitogen-activated protein kinase (MAPK) signaling pathways. Murine macrophages (RAW 264.7) undergo apoptosis following serum deprivation, as determined by DNA laddering assay. However, apoptosis is prevented in serum-deprived macrophages by the presence of exogenous TGF-beta(1). Using stably transfected RAW 264.7 cells with the kinase-deleted dominant-negative mutant of T beta R-II (T beta R-IIM) cDNA, we demonstrate that this protective effect by TGF-beta(1) is completely abrogated. To determine the downstream signaling pathways, we examined TGF-beta(1) effects on the MAPK pathway. We show that TGF-beta(1) induces the extracellular signal-regulated kinase (ERK) activity in a time-dependent manner up to 4 h after stimulation. Furthermore, TGF-beta(1) does not rescue serum deprivation-induced apoptosis in RAW 264.7 cells transfected with a dominant-negative mutant MAPK (ERK2) cDNA or in wild type RAW 264.7 cells in the presence of the MAPK kinase (MEK1) inhibitor. Taken together, our data demonstrate for the first time that TGF-beta(1) is an inhibitor of apoptosis in cultured macrophages and may serve as a cell survival factor via T beta R-II-mediated signaling and downstream intracellular MAPK signaling pathway.