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首页> 外文期刊>Biochemistry >The Common #gamma# Chain (#gamma#c) Is a Required Signaling Component of the IL-21 Receptor and Supports IL-21-Induced Cell proliferation via JAK3
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The Common #gamma# Chain (#gamma#c) Is a Required Signaling Component of the IL-21 Receptor and Supports IL-21-Induced Cell proliferation via JAK3

机译：通用＃gamma＃链（＃gamma＃c）是IL-21受体的必需信号成分，并通过JAK3支持IL-21诱导的细胞增殖。

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The common cytokine receptor y chain (#gamma#c), an essential component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is critical for the development and function of lymphocytes. Recently, a novel lymphokine (IL-21 ) and its receptor (IL-21R#alpha#) were descended which profoundly affect the growth and activation state of B, T, and NK cells in concert with other lymphoklnes or stimuli [Pamsh-Novak, J., et al. (2000) Nature 408, 57-63]. In this report, we show that #gamma#c is also a required signaling component of the IL-ZI receptor (IL-ZIR) using the #gamma#c-deficient X-linked severe combined immunodeficiency (XSCID) lymphoblastoid cell line JT, and JT cells reconstituted with #gamma#c (JT/#gamma#c). Moreover, we demonstrate a functional requirement for both #gamma#c and the #gamma#c-associated Janus family tyrosine kinase 3 (JAK3) in IL-ZI-induced proliferation of pro-B-lymphoid cells engineered to express human IL-ZIR#alpha# (BaF3/IL-ZIR#alpha#). Retroviral-mediated transduction of wild-type #gamma#c into XSCID JT cells restored function to the IL-21R, as shown by IL-ZI-induced tyrosine phospborylation of JAKI and JAK3, and downstream activation of STATS, in JT/#gamma#c cells as well as BaF3/IL-ZIR#alpha# and primary splenic Bcells. In contrast, IL-21 failed to activate the JAK-STAT pathway in nonreconstituted JT cells. Monoclonal antibodies specific for the #gamma#c chain effectively inhibited IL-ZI -induced growth of BaF3/IL-21R#alpha# cells, supporting a functional role for this molecule in the IL-ZIR complex. In addition, the specific JAK3tyrosine kinase inhibitor WHI-P131 significantly reduced IL-21-induced proliferation of BaF3ilL-21R#alpha# cells. Taken together, these results definitively demonstrate that IL-21-mediated signaling requires the #gamma#c chain, and indicate that JAK3is an essential transducer of #gamma#c-dependent survival an(1/or mitogenic signals induced by this cytokine.
机译：常见的细胞因子受体y链（＃gamma＃c）是IL-2，IL-4，IL-7，IL-9和IL-15受体的重要组成部分，对淋巴细胞的发育和功能至关重要。最近，一种新的淋巴因子（IL-21）及其受体（IL-21R＃alpha＃）下降了，它与其他淋巴因子或刺激物协同作用深刻影响B，T和NK细胞的生长和活化状态[Pamsh-Novak ，J。等。 （2000）Nature 408，57-63]。在这份报告中，我们证明了＃gamma＃c也是使用＃gamma＃c缺陷X连锁严重联合免疫缺陷症（XSCID）淋巴母细胞样细胞系JT的IL-ZI受体（IL-ZIR）的必需信号传导成分，和用＃gamma＃c（JT /＃gamma＃c）重构的JT细胞。此外，我们证明了IL-ZI诱导的工程化表达人IL-ZIR的前B淋巴样细胞增殖中＃gamma＃c和与＃gamma＃c相关的Janus家族酪氨酸激酶3（JAK3）的功能需求＃alpha＃（BaF3 / IL-ZIR＃alpha＃）。逆转录病毒介导的野生型＃gamma＃c向XSCID JT细胞的转导恢复了IL-21R的功能，如IL-ZI诱导的JAKI和JAK3酪氨酸磷酸化以及STATS在JT /＃gamma中的下游激活所示。 #c细胞以及BaF3 / IL-ZIR＃alpha＃和原发性脾脏B细胞。相反，IL-21在未重建的JT细胞中未能激活JAK-STAT途径。对＃γ＃c链具有特异性的单克隆抗体可有效抑制IL-ZI诱导的BaF3 / IL-21R＃alpha＃细胞生长，从而支持该分子在IL-ZIR复合物中的功能性作用。另外，特异性JAK3酪氨酸激酶抑制剂WHI-P131显着降低IL-21诱导的BaF3ilL-21R＃α＃细胞的增殖。综上所述，这些结果明确证明IL-21介导的信号传导需要＃gamma＃c链，并表明JAK3是这种细胞因子诱导的＃gamma＃c依赖性生存和/或促有丝分裂信号的必不可少的换能器。

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