Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathway.
Tyrosine phosphorylation of Vav stimulates IL-6 production in mast cells by a Rac/c-Jun N-terminal kinase-dependent pathway.
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DOI：
10.4049/jimmunol.163.2.802
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发表时间：
1999-07
影响因子：
4.4
通讯作者：
J. S. Song;H. Haleem‐Smith;R. Arudchandran;J. Gómez;P. M. Scott;J. Mill;T. Tan;J. Rivera
中科院分区：
文献类型：
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作者：
J. S. Song;H. Haleem‐Smith;R. Arudchandran;J. Gómez;P. M. Scott;J. Mill;T. Tan;J. Rivera
本研究探讨了Vav的鸟嘌呤核苷酸交换活性是否与肥大细胞中细胞因子的产生有关。在RBL-2H3肥大细胞系中，Vav的过表达导致了组成型酪氨酸磷酸化和Vav的激活。我们分析了Vav过表达对细胞因子产生的功能影响。在vav过表达细胞中，IL-2和IL-6 mRNA水平显著升高，并与NF-AT活性升高相关。对IL-3、IL-4、GM-CSF、tnf - α和tgf - β mRNA水平的影响很小或没有影响。FcepsilonRI没有进一步提高IL-2和IL-6 mRNA水平，仅轻微提高NF-AT活性，但显著提高了其他被测细胞因子的mRNA水平。为了了解所需的信号转导，我们主要通过测量丝裂原激活的蛋白激酶活性，并分析突变或显性阴性形式的Vav， Rac1和c-Jun n-末端激酶1 （JNK1）的影响来研究IL-6诱导。Vav过表达导致JNK1的组成性激活，而对p38丝裂原活化蛋白激酶和ERK2的影响很小或没有影响。这依赖于Vav介导的Rac1激活，作为Dbl结构域突变的Vav，失活的Rac N17和失活的JNK1下调了Vav诱导的JNK1或IL-6反应。在FcepsilonRI作用下，表达Vav，而不表达结构域突变的Vav，增加了非永生化骨髓源肥大细胞分泌IL-6。我们得出结论，Vav磷酸化有助于肥大细胞中IL-6的诱导。
This study investigates whether the guanine nucleotide exchange activity of Vav is linked to cytokine production in mast cells. Overexpression of Vav in the RBL-2H3 mast cell line resulted in the constitutive tyrosine phosphorylation and activation of Vav. We analyzed the functional effect of Vav overexpression on cytokine production. IL-2 and IL-6 mRNA levels were dramatically increased in Vav-overexpressing cells and correlated with increased NF-AT activity. Little or no effect was observed on the mRNA levels of IL-3, IL-4, GM-CSF, TNF-alpha, and TGF-beta. FcepsilonRI engagement did not further enhance IL-2 and IL-6 mRNA levels and only slightly enhanced NF-AT activity, but dramatically increased the mRNA levels of other tested cytokines. To understand the signal transduction required, we focused primarily on IL-6 induction by measuring mitogen-activated protein kinase activity and analyzing the effects of mutant or dominant negative forms of Vav, Rac1, and c-Jun N-terminal kinase-1 (JNK1). Vav overexpression resulted in the constitutive activation of JNK1 with little or no effect on p38 mitogen-activated protein kinase and ERK2. This was dependent on Vav-mediated activation of Rac1 as a Dbl domain-mutated Vav, inactive Rac N17, and inactive JNK1 down-regulated the Vav-induced JNK1 or IL-6 responses. Vav expression, but not expression of domain-mutated Vav, increased IL-6 secretion from nonimmortalized bone marrow-derived mast cells upon FcepsilonRI engagement. We conclude that Vav phosphorylation contributes to IL-6 induction in mast cells.