Negative regulation of IL-1 2/STAT4 induced signal transduction

IL-12促进T细胞和NK细胞的增殖，在诱导Th -1分化中起关键作用。IL-12通过激活受体相关的JAK家族激酶和STAT4介导其生物活性，STAT4被募集到人IL-12受体β2亚基（IL-12Rβ2）中磷酸化的Tyr-800。本研究表明，细胞因子信号传导抑制因子-3 （SOCS-3）也通过SOCS-3 SH2结构域和IL-12Rβ2中磷酸化的tyr1 -800的相互作用被募集到IL-12Rβ2中。此外，SOCS-3抑制il -12诱导的STAT4的DNA结合激活和转录活性，而不是其SH2结构域缺陷突变体。这些结果表明，在Th2细胞中高水平表达的SOCS-3通过结合IL-12Rβ2中STAT4的对接位点，对STAT4介导的IL-12信号通路起到抑制作用，从而提出了SOCS-3可能在Th分化中发挥调节作用的可能性。此外，IL-12在人淋巴细胞中诱导蛋白酶体依赖性的STAT4蛋白水解和STAT4和JAK2的泛素化。泛素-蛋白酶体通路可能负调控酪氨酸JAK2和STAT4在IL-12信号通路中的作用。

IL-12 promotes the proliferation of T cells as well as NK cells and plays a critical role in induction of the Th 1 differentiation. IL-12 mediates its biological activities through activation of the receptor-associated JAK family kinases and STAT4, which is recruited to phosphorylated Tyr-800 in the human IL-12 receptor β2 subunit (IL-12Rβ2). Here we demonstrate that suppressor of cytokine signaling-3 (SOCS-3) is also recruited to IL-12Rβ2 by the interaction involving the SOCS-3 SH2 domain and phosphorylated Tyr-800 in IL-12Rβ2. Furthermore, SOCS-3, but not its SH2 domain-defective mutant, inhibited the IL-12-induced activation of DNA binding and transcriptional activities of STAT4. These results suggest that SOCS-3, expressed at high levels in Th2 cells, plays an inhibitory role in STAT4-mediated IL-12 signaling by binding to the STAT4 docking site in IL-12Rβ2, thus raising a possibility that SOCS-3 may play a role in regulation of Th differentiation. Also, IL-12 induces proteasome-dependent proteolysis of STAT4 and ubiquitination of STAT4 and JAK2 in human lymphocytes. Ubiquitin-proteasome pathway may negatively regulates tyrosine JAK2 and STAT4 in IL-12 signaling.