The role of p44/42 activation in tributyltin-induced inhibition of human natural killer cells: effects of MEK inhibitors.
The role of p44/42 activation in tributyltin-induced inhibition of human natural killer cells: effects of MEK inhibitors.
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DOI：
10.1002/jat.1397
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发表时间：
2009-03
影响因子：
3.3
通讯作者：
Whalen, Margaret M.
中科院分区：
文献类型：
--
作者：
Abraha, Abraham B.;Whalen, Margaret M.
肿瘤细胞的破坏是NK细胞的关键功能。先前的研究表明，三丁基锡（TBT）可以显着降低人类NK细胞的溶解功能，伴随着有丝分裂原活化蛋白激酶（MAPK），p44/42的磷酸化（活化）状态的增加。目前的研究通过使用MAPK激酶（MEK）抑制剂PD 98059和U 0126来检查p44/42活化在TBT诱导的NK溶解功能降低中的作用。用PD 98059或U 0126或两者处理1小时降低NK细胞裂解K562肿瘤细胞的能力。PD 98059、U 0126或两种抑制剂的组合能够完全阻断TBT诱导的p44/42活化。然而，当p44/42激活被PD 98059、U 0126或其组合阻断时，随后暴露于TBT仍然能够降低NK细胞的溶解功能。这些结果表明，TBT诱导的p44/42的激活通过其上游激活剂MEK的激活而发生，而不是通过TBT诱导的p44/42磷酸酶活性的抑制。此外，由于溶解功能从未被MEK抑制剂完全阻断，因此结果表明p44/42途径的激活并不是新鲜分离的人NK细胞溶解功能激活的唯一原因。最后，结果表明，TBT诱导的p44/42激活并不是唯一导致溶解功能丧失的原因。
Destruction of tumor cells is a key function of NK cells. Previous studies have shown that tributyltin (TBT) can significantly reduce the lytic function of the human NK cells with accompanying increases in the phosphorylation (activation) states of the mitogen activated protein kinases (MAPKs), p44/42. The current studies examine the role of p44/42 activation in the TBT-induced reduction of NK-lytic function, by using MAPK kinase (MEK) inhibitors, PD98059 and U0126. A 1 h treatment with PD98059 or U0126 or both decreased the ability of NK cells to lyse K562 tumor cells. PD98059, U0126 or a combination of both inhibitors were able to completely block TBT-induced activation of p44/42. However, when p44/42 activation was blocked by the presence of PD98059, U0126, or the combination, subsequent exposure to TBT was still able to decrease the lytic function of NK cells. These results indicate that TBT-induced activation of p44/42 occurs via the activation of its upstream activator, MEK, and not by a TBT-induced inhibition of p44/42 phosphatase activity. Additionally, as lytic function was never completely blocked by MEK inhibitors, the results indicate that activation of p44/42 pathway is not solely responsible for the activation of lytic function of freshly isolated human NK cells. Finally, the results showed that TBT-induced activation of p44/42 is not solely responsible for the loss of lytic function.
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