PKCε is involved in JNK activation that mediates LPS-induced TNF-α, which induces apoptosis in macrophages
PKCε is involved in JNK activation that mediates LPS-induced TNF-α, which induces apoptosis in macrophages
复制标题
DOI：
10.1152/ajpcell.00228.2003
复制
发表时间：
2003-11-01
影响因子：
5.5
通讯作者：
Celada, A
中科院分区：
文献类型：
--
作者：
Comalada, N;Xaus, J;Celada, A
脂多糖（LPS）是巨噬细胞的强力刺激物，可诱导巨噬细胞凋亡。利用骨髓源性巨噬细胞的原代培养，我们发现肿瘤坏死因子- α (tnf - α)的自分泌在lps诱导的细胞凋亡中起主要作用。LPS激活PKC并调节不同的丝裂原活化蛋白激酶（MAPK）。我们的目的是确定其参与分泌tnf - α或诱导细胞凋亡。利用特异性抑制剂和PKCepsilon基因被破坏的小鼠，我们发现lps诱导的tnf - α依赖性凋亡主要是由PKCepsilon介导的，它不直接参与凋亡的信号机制，而是参与tnf - α分泌的过程。在我们的细胞模型中，这三种MAPKs都参与调节tnf - α的分泌，但水平不同。JNK主要调控tnf - α转录和细胞凋亡，而ERK和p38可能通过转录后机制调控tnf - α的产生。只有JNK的活性是由PKCepsilon介导的，因此在tnf - α分泌和LPS诱导的细胞凋亡中起主要作用。我们在巨噬细胞中证明，涉及PKCepsilon的LPS调节JNK活性并产生tnf - α，从而诱导细胞凋亡。
Lipopolysaccharide (LPS) is a powerful stimulator of macrophages and induces apoptosis in these cells. Using primary cultures of bone marrow-derived macrophages, we found that the autocrine production of tumor necrosis factor-alpha (TNF-alpha) has a major function in LPS-induced apoptosis. LPS activates PKC and regulates the different mitogen-activated protein kinases (MAPK). We aimed to determine its involvement either in the secretion of TNF-alpha or in the induction of apoptosis. Using specific inhibitors and mice with the gene for PKCepsilon disrupted, we found that LPS-induced TNF-alpha-dependent apoptosis is mostly mediated by PKCepsilon, which is not directly involved in the signaling mechanism of apoptosis but rather in the process of TNF-alpha secretion. In our cell model, all three MAPKs were involved in the regulation of TNF-alpha secretion, but at different levels. JNK mainly regulates TNF-alpha transcription and apoptosis, whereas ERK and p38 contribute to the regulation of TNF-alpha production, probably through posttranscriptional mechanisms. Only JNK activity is mediated by PKCepsilon in response to LPS and so plays a major role in TNF-alpha secretion and LPS-induced apoptosis. We demonstrated in macrophages that LPS involving PKCepsilon regulates JNK activity and produces TNF-alpha, which induces apoptosis.