Sengupta T K, Schmitt E M, Ivashkiv L B
Department of Medicine, Hospital for Special Surgery, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9499-504. doi: 10.1073/pnas.93.18.9499.
An important component of cytokine regulation of cell growth and differentiation is rapid transcriptional activation of genes by the JAK-STAT (signal transducer and activator of transcription) signaling pathway. Ligation of cytokine receptors results in tyrosine phosphorylation and activation of receptor-associated Jak protein tyrosine kinases and cytoplasmic STAT transcription factors, which then translocate to the nucleus. We describe the interruption of cytokine triggered JAK-STAT signals by cAMP, the calcium ionophore ionomycin, and granulocyte/macrophage colony-stimulating factor. Jak1 kinase activity, interleukin 6-induced gene activation, Stat3 tyrosine phosphorylation, and DNA-binding were inhibited, as was activation of Jak1 and Stat1 by interferon gamma. The kinetics and requirement for new RNA and protein synthesis for inhibition of interleukin 6 by ionomycin and GM-CSF differed, but both agents increased the association of Jak1 with protein tyrosine phosphatase ID (SH2-containing phosphatase 2). Our results demonstrate that crosstalk with distinct signaling pathways can inhibit JAK-STAT signal transduction, and suggest approaches for modulating cytokine activity during immune responses and inflammatory processes.
细胞因子对细胞生长和分化的调节作用的一个重要组成部分是JAK-STAT（信号转导子和转录激活子）信号通路对基因的快速转录激活。细胞因子受体的连接导致酪氨酸磷酸化以及与受体相关的Jak蛋白酪氨酸激酶和细胞质STAT转录因子的激活，随后它们转移至细胞核。我们描述了cAMP、钙离子载体离子霉素和粒细胞/巨噬细胞集落刺激因子对细胞因子触发的JAK-STAT信号的阻断作用。Jak1激酶活性、白细胞介素6诱导的基因激活、Stat3酪氨酸磷酸化和DNA结合均受到抑制，干扰素γ对Jak1和Stat1的激活作用也受到抑制。离子霉素和粒细胞/巨噬细胞集落刺激因子抑制白细胞介素6的作用对新RNA和蛋白质合成的动力学及需求有所不同，但这两种试剂均增加了Jak1与蛋白酪氨酸磷酸酶ID（含SH2结构域的磷酸酶2）的结合。我们的结果表明，与不同信号通路的相互作用可抑制JAK-STAT信号转导，并提示了在免疫反应和炎症过程中调节细胞因子活性的方法。
