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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >Novel PKC signaling is required for LPS-induced soluble Flt-1 expression in macrophages.
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Novel PKC signaling is required for LPS-induced soluble Flt-1 expression in macrophages.

机译：LPS诱导巨噬细胞中可溶性Flt-1表达需要新型PKC信号传导。

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摘要

In vitro activation of macrophages by LPS induces rapid release of vascular endothelial growth factor (VEGF) and soluble fms-like tyrosine kinase-1 receptor (sFlt-1), which are thought to be the effectors to cause sepsis. However, the signal pathway that controls the VEGF and sFlt-1 expressions in LPS-activated macrophages remains unclear. In this study, we demonstrated that phosphorylation of protein kinase C (PKC)delta played a key role in the VEGF and sFlt-1 signaling pathway of LPS-activated macrophages. PKC is a family of serine-threonine kinases, which are classified into three major groups based on homology and cofactor requirements: conventional PKCs, novel PKCs, and atypical PKCs. In the murine RAW264.7 cells, as well as in primary human monocytes/macrophages, pretreatment with a general PKC inhibitor GF109203X or with a novel PKCdelta inhibitor rottlerin or overexpression of a kinase-inactive form of PKCdelta (K376R) eliminated LPS-induced sFlt-1 expression and augmented LPS-induced VEGF expression at the protein and the transcription levels. In contrast, Go6976, an inhibitor for the conventional PKCs, or myristoylated PKCzeta pseudosubstrate peptide, an inhibitor for the atypical PKCs, failed to exert the same effects. These data suggest that PKCdelta signaling is involved in LPS-induced sFlt-1 expression and serves as a negative mediator in LPS-induced VEGF expression in macrophages. A novel strategy controlling the LPS-induced PKC pathways, especially the PKCdelta isoform, may be developed based on this study.
机译：LPS对巨噬细胞的体外激活诱导血管内皮生长因子（VEGF）和可溶性fms样酪氨酸激酶1受体（sFlt-1）的快速释放，这被认为是引起败血症的效应子。但是，控制LPS激活的巨噬细胞中VEGF和sFlt-1表达的信号途径仍不清楚。在这项研究中，我们证明了蛋白激酶C（PKC）δ的磷酸化在LPS激活的巨噬细胞的VEGF和sFlt-1信号通路中起着关键作用。 PKC是丝氨酸-苏氨酸激酶家族，根据同源性和辅因子要求可分为三大类：常规PKC，新型PKC和非典型PKC。在鼠类RAW264.7细胞以及原代人单核细胞/巨噬细胞中，用通用PKC抑制剂GF109203X或新型PKCdelta抑制剂rottlerin预处理或过表达激酶非活性形式的PKCdelta（K376R）可以消除LPS诱导的sFlt -1表达和LPS诱导的VEGF在蛋白质和转录水平的表达增加。相反，Go6976是常规PKC的抑制剂，或肉豆蔻酰化的PKCzeta假底物肽，是非典型PKC的抑制剂，未能发挥相同的作用。这些数据表明，PKCdelta信号传导参与LPS诱导的sFlt-1表达，并在巨噬细胞中充当LPS诱导的VEGF表达的阴性介质。基于这项研究，可以开发出一种控制LPS诱导的PKC途径，特别是PKCdelta亚型的新策略。

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