The src family-selective tyrosine kinase inhibitor PP1 blocks LPS and IFN-γ-mediated TNF and iNOS production in murine macrophages
The src family-selective tyrosine kinase inhibitor PP1 blocks LPS and IFN-γ-mediated TNF and iNOS production in murine macrophages
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DOI：
10.1097/00024382-199911000-00004
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发表时间：
1999-11-01
期刊：
影响因子：
3.1
通讯作者：
English, BK
中科院分区：
文献类型：
--
作者：
Orlicek, SL;Hanke, JH;English, BK
酪氨酸磷酸化途径是巨噬细胞激活过程以及由此产生的炎症介质（例如肿瘤坏死因子（TNF）和一氧化氮（NO））的重要组成部分。多项证据表明，蛋白酪氨酸激酶 src 家族的成员在革兰氏阴性细菌脂多糖 (LPS) 或细胞因子干扰素-γ (IFN-gamma) 的巨噬细胞激活中发挥重要作用，但在小鼠中靶向破坏 src 家族的三个成员（hck、fgr 和 lyn）未能证明巨噬细胞激活中这些特定激酶的需要。 src 家族选择性酪氨酸激酶抑制剂，可有效抑制经 LPS、rIFN-gamma 或 LPS + rIFN-gamma 刺激的 RAW 264.7 小鼠巨噬细胞中 TNF 和诱导型一氧化氮合酶 (iNOS) 的产生。此外，测试浓度的PP1抑制LPS和rIFN-γ介导的hck酪氨酸激酶及其推定底物vav的酪氨酸磷酸化，但不能阻断rIFN-γ介导的JAK2酪氨酸磷酸化。这些发现为涉及一种或多种 src 相关激酶的巨噬细胞激活模型提供了额外的支持。应在脓毒症动物模型中研究该信号通路的选择性抑制剂。
Tyrosine phosphorylation pathways are essential components of the process of macrophage activation and the resultant production of inflammatory mediators such as tumor necrosis factor (TNF) and nitric oxide (NO). Several lines of evidence suggest that members of the src family of protein tyrosine kinases play important roles in macrophage activation by gram-negative bacterial lipopolysaccharide (LPS) or the cytokine interferon-gamma (IFN-gamma), but targeted disruption of three members of the src family (hck, fgr, and lyn) in mice failed to demonstrate a requirement for these particular kinases in macrophage activation, We report that the pyrazolopyrimidine PP1, a src family-selective tyrosine kinase inhibitor, potently inhibits the production of TNF and inducible nitric oxide synthase (iNOS) in RAW 264.7 murine macrophages stimulated with LPS, rIFN-gamma, or LPS + rIFN-gamma. Furthermore, the tested concentrations of PP1 inhibit LPS- and rIFN-gamma-mediated tyrosine phosphorylation of the hck tyrosine kinase and its putative substrate, vav, but fail to block rIFN-gamma-mediated JAK2 tyrosine phosphorylation. These findings provide additional support for a model of macrophage activation involving one or more src-related kinases. Selective inhibitors of this signaling pathway should be studied in animal models of sepsis.