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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：共同的γ链（γc）是IL-21受体的必需信号组件，并通过JAK3支持IL-21诱导的细胞增殖。

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摘要

The common cytokine receptor gamma 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 described which profoundly affect the growth and activation state of B, T, and NK cells in concert with other lymphokines or stimuli [Parrish-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-21 receptor (IL-21R) 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-21-induced proliferation of pro-B-lymphoid cells engineered to express human IL-21R alpha (BaF3/IL-21R alpha). Retroviral-mediated transduction of wild-type gamma c into XSCID JT cells restored function to the IL-21R, as shown by IL-21-induced tyrosine phosphorylation of JAK1 and JAK3, and downstream activation of STAT5, in JT/gamma c cells as well as BaF3/IL-21R alpha and primary splenic B cells. 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-21-induced growth of BaF3/IL-21R alpha cells, supporting a functional role for this molecule in the IL-21R complex. In addition, the specific JAK3 tyrosine kinase inhibitor WHI-P131 significantly reduced IL-21-induced proliferation of BaF3/IL-21R alpha cells. Taken together, these results definitively demonstrate that IL-21-mediated signaling requires the gamma c chain, and indicate that JAK3 is an essential transducer of gamma c-dependent survival and/or mitogenic signals induced by this cytokine.
机译：常见的细胞因子受体γ链（γc）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，描述了一种新型淋巴因子（IL-21）及其受体（IL-21R alpha），它们与其他淋巴因子或刺激物协同作用，深刻影响B，T和NK细胞的生长和激活状态[Parrish-Novak，J等。 （2000）Nature 408，57-63]。在此报告中，我们显示了γc也是使用γc缺乏的X连锁严重联合免疫缺陷（XSCID）淋巴母细胞系JT和重建的JT细胞构成的IL-21受体（IL-21R）的必需信号传导成分。带有伽玛C（JT /伽玛C）。此外，我们证明了IL-21诱导的工程表达人IL-21R alpha（BaF3 / B的前B淋巴样细胞增殖）中对γc和与γc相关的Janus家族酪氨酸激酶3（JAK3）的功能需求IL-21R alpha）。逆转录病毒介导的野生型γC到XSCID JT细胞的转导恢复了IL-21R的功能，如IL-21诱导JAK1和JAK3的酪氨酸磷酸化以及STAT5在JT /γc细胞中的下游激活所示。以及BaF3 / IL-21Rα和原代脾脏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γc链具有特异性的单克隆抗体可有效抑制IL-21诱导的BaF3 / IL-21Rα细胞的生长，从而支持该分子在IL-21R复合物中的功能性作用。此外，特定的JAK3酪氨酸激酶抑制剂WHI-P131显着降低了IL-21诱导的BaF3 / IL-21Rα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γc链，并表明JAK3是该细胞因子诱导的γc依赖性生存和/或促有丝分裂信号的重要转导者。

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