Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes.
Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes.
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DOI：
10.4049/jimmunol.151.12.6692
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发表时间：
1993-12
影响因子：
4.4
通讯作者：
Y. Geng;Baoping Zhang;M. Lotz
中科院分区：
文献类型：
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作者：
Y. Geng;Baoping Zhang;M. Lotz
细菌 LPS 诱导单核吞噬细胞产生 IL-1、IL-6 和 TNF 等细胞因子，这是败血性休克综合征发病机制的核心组成部分。然而，LPS 激活这些细胞表达细胞因子的机制尚未完全表征。本研究探讨了不同蛋白激酶在 LPS 诱导细胞因子中的作用。结果表明，LPS 诱导 IL-1β、IL-6 和 TNF-α mRNA 水平增加 12 至 16 倍，而这种增加可被蛋白酪氨酸激酶特异性抑制剂除草霉素 A 和金雀异黄素（浓度分别为 1.7 和 37 µM）完全或超过 80% 阻断。星形孢菌素对蛋白激酶 C 的抑制作用降低了 LPS 对 TNF-α 的诱导，但对 IL-6 和 IL-1 β 没有影响。 H89 对蛋白激酶 A 的抑制降低了 IL-6 mRNA 水平，但未检测到改变 IL-1 β 或 TNF-α mRNA 水平。相比之下，LPS 不会增加白血病抑制因子 mRNA，白血病抑制因子 mRNA 是组成型表达的，并且不会被这些抑制剂显着减少。除了细胞因子 mRNA 水平外，PTK 抑制剂除草霉素 A 和金雀异黄酮也将 LPS 诱导的 IL-6 蛋白合成和 IL-6 生物活性降低至基线水平。两种 PTK 抑制剂还降低了核因子 kappa B (NF-kappa B) 的 LPS 激活，核因子 kappa B 是一种参与 IL-6 和 TNF-α 等细胞因子基因表达的转录因子。 H89 也降低了 NF-κ B 的激活，而星形孢菌素对此反应没有影响。总之，这些发现表明蛋白激酶 C 和蛋白激酶 A 似乎对 LPS 诱导细胞因子具有选择性作用，而 PTK 是 LPS 诱导广谱细胞因子和单核细胞中 NF-κ B 激活所必需的。
Bacterial LPS induce production of cytokines such as IL-1, IL-6, and TNF in mononuclear phagocytes, and this represents a central component in the pathogenesis of septic shock syndrome. However, the mechanisms by which LPS activates these cells to express cytokines are not completely characterized. The present study addressed the role of different protein kinases in the LPS induction of cytokines. It is shown that LPS induced a 12- to 16-fold increase in IL-1 beta, IL-6, and TNF-alpha mRNA levels, and this was completely or more than 80% blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1.7 and 37 microM, respectively. Protein kinase C inhibition by staurosporine reduced LPS induction of TNF-alpha, whereas it had no effects on IL-6 and IL-1 beta. Inhibition of protein kinase A by H89 reduced IL-6 mRNA levels but did not detectably change IL-1 beta or TNF-alpha mRNA levels. In contrast, LPS did not increase leukemia inhibitory factor mRNA, which was constitutively expressed and not significantly reduced by these inhibitors. In addition to cytokine mRNA levels, LPS-induced IL-6 protein synthesis and IL-6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein. Both PTK inhibitors also reduced the LPS activation of nuclear factor-kappa B (NF-kappa B), which is a transcription factor involved in the expression of cytokine genes such as IL-6 and TNF-alpha. The activation of NF-kappa B was also reduced by H89, whereas staurosporine had no effect on this response. In summary, these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines, whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF-kappa B activation in monocytes.