Resistance to TNF-alpha cytotoxicity can be achieved through different signaling pathways in rat mesangial cells.
Resistance to TNF-alpha cytotoxicity can be achieved through different signaling pathways in rat mesangial cells.
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大鼠肾小球系膜细胞可通过不同的信号传导途径实现对 TNF-α 细胞毒性的抵抗。
DOI：
10.1152/ajpcell.1999.276.2.c435
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Williamson,JR
中科院分区：
文献类型：
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作者：
Guo,YL;Kang,B;Williamson,JR
我们之前报道了Ro-318220阻断肿瘤坏死因子-α (TNF-α)诱导的丝裂原活化蛋白激酶磷酸酶-1 （MKP-1）的表达，随后引起系膜细胞凋亡(y - l。郭，康B.， J. R. williamson。医学杂志。化学通报，2009(3):362 - 366。这些数据支持了我们的假设，即TNF-α-诱导的磷酸酶可能负责阻止c-Jun nh2末端蛋白激酶（JNK）的持续激活和随后的细胞死亡。郭，K. Baysal， B. Kang, l - j。J. R.威廉森。医学杂志。化学通报，2004(5):387 - 398。在这项研究中，我们研究了蛋白激酶C （PKC）参与调节系膜细胞中MKP-1的表达及其对生存能力的影响。虽然最初被描述为PKC抑制剂，但Ro-318220通过阻断PKC途径以外的机制抑制TNF-α-诱导的MKP-1表达。此外，抑制PKC通路既不显著影响TNF-α诱导的MKP-1表达，也不使细胞对TNF-α的毒性作用敏感。因此，PKC激活对于细胞实现对正常系膜细胞所表现的TNF-α细胞毒性的抗性并不是必需的。然而，12-肉豆蔻酸13-醋酸酯（PMA）激活PKC可显著增加细胞对TNF-α凋亡作用的抵抗。巧合的是，PMA刺激MKP-1的表达，抑制JNK的激活。因此，PMA诱导的MKP-1表达可能与PMA的保护作用有关。这些结果为先前的PKC激活可以拯救一些细胞免于凋亡提供了机制解释。
We reported previously that Ro-318220 blocked expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) induced by tumor necrosis factor-α (TNF-α) and subsequently caused apopotosis in mesangial cells (Y.-L. Guo, B. Kang, and J. R. Williamson.J. Biol. Chem.273: 10362–10366, 1998). These data support our hypothesis that a TNF-α-inducible phosphatase may be responsible for preventing sustained activation of c-Jun NH2-terminal protein kinase (JNK) and consequent cell death in these cells (Y.-L. Guo, K. Baysal, B. Kang, L.-J. Yang, and J. R. Williamson.J. Biol. Chem.273: 4027–4034, 1998). In this study, we investigated the involvement of protein kinase C (PKC) in regulation of MKP-1 expression in mesangial cells together with effects on viability. Although originally characterized as a PKC inhibitor, Ro-318220 inhibited TNF-α-induced MKP-1 expression through a mechanism other than blocking the PKC pathway. Furthermore, inhibition of the PKC pathway neither significantly affected TNF-α-induced MKP-1 expression nor made cells susceptible to toxic effect of TNF-α. Thus PKC activation is not essential for cells to achieve the resistance to TNF-α cytotoxicity displayed by normal mesangial cells. However, activation of PKC by phorbol 12-myristate 13-acetate (PMA) dramatically increased cellular resistance to the apoptotic effect of TNF-α. Coincidentally, PMA stimulated MKP-1 expression and suppressed JNK activation. Therefore, PMA-induced MKP-1 expression may contribute to the protective effect of PMA. These results provide a mechanistic explanation for previous documentation that PKC activation can rescue some cells from apopotosis.