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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >A selective inhibitor of p38 MAP kinase, SB202190, induced apoptotic cell death of a lipopolysaccharide-treated macrophage-like cell line, J774.1
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A selective inhibitor of p38 MAP kinase, SB202190, induced apoptotic cell death of a lipopolysaccharide-treated macrophage-like cell line, J774.1

机译：p38 MAP激酶的选择性抑制剂SB202190诱导了脂多糖处理的巨噬细胞样细胞系J774.1的凋亡。

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摘要

A selective p38 MAP kinase (p38 MAPK) inhibitor, SB202190, induced apoptotic cell death of a macrophage-like cell line, J774.1, in the presence of lipopolysaccharide (LPS), as judged by DNA nicks revealed by terminal deoxy transferase (TdT)-mediated dUTP nick end labeling (TUNEL), activation of caspase-3, and subsequent release of lactate dehydrogenase. This cytotoxicity was dependent on both LPS and SB202190, and such inhibitors of the upstream LPS-signaling cascade as polymyxin B and TPCK blocked this macrophage cell death. SB202190 suppressed the kinase activity of p38, leading to inhibition of activation of MAPKAPK2 and then the subsequent phosphorylation of hsp27 in LPS-treated macrophages both in vitro and in vivo, but an inactive analog of SB202190, SB202474, did not. There was a threshold of the time of addition of SB202190 to LPS-treated macrophages to induce apoptosis, which was before full transmission of p38 activity to a direct downstream kinase, MAPKAPK2. Besides, localization of phosphorylated hsp27 in Golgi area of the LPS-treated macrophages was suppressed by SB202190, while it was not by SB202474. These results suggest that selective inhibition of p38 MAPK activity in LPS-induced MAP kinase cascade leads to apoptosis of macrophages.
机译：选择性p38 MAP激酶（p38 MAPK）抑制剂SB202190在存在脂多糖（LPS）的情况下诱导巨噬细胞样细胞系J774.1的凋亡，这由末端脱氧转移酶（TdT）揭示的DNA缺口来判断。介导的dUTP缺口末端标记（TUNEL），caspase-3的激活以及随后的乳酸脱氢酶的释放。这种细胞毒性取决于LPS和SB202190，上游LPS信号级联反应的抑制剂如多粘菌素B和TPCK阻止了该巨噬细胞的死亡。 SB202190抑制了p38的激酶活性，导致抑制了MAPKAPK2的激活，随后抑制了LPS处理的巨噬细胞在体内和体外的hsp27磷酸化，但SB202190的失活类似物SB202474却没有。在将p38活性完全传递给直接下游激酶MAPKAPK2之前，存在将SB202190加入LPS处理的巨噬细胞以诱导凋亡的时间阈值。此外，磷酸化的hsp27在LPS处理的巨噬细胞的高尔基区的定位被SB202190抑制，而未被SB202474抑制。这些结果表明，LPS诱导的MAP激酶级联反应中p38 MAPK活性的选择性抑制导致巨噬细胞凋亡。

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