The Src-protein tyrosine kinase Lck is required for IL-1-mediated costimulatory signaling in Th2 cells
The Src-protein tyrosine kinase Lck is required for IL-1-mediated costimulatory signaling in Th2 cells
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DOI：
10.4049/jimmunol.167.12.6827
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发表时间：
2001-12-15
影响因子：
4.4
通讯作者：
Bothwell, ALM
中科院分区：
文献类型：
--
作者：
al-Ramadi, BK;Welte, T;Bothwell, ALM
Src 蛋白酪氨酸激酶与 T 淋巴细胞中 TCR 启动的信号传导密切相关。该家族的成员之一 Lek 也参与 Th1 细胞中 CD28 介导的共刺激。在 Th2 淋巴细胞中，IL-1 与 I 型 IL-1R (IL-IRI) 的相互作用也可以提供共刺激信号，最终激活 NF-kappaB 转录因子。然而，IL-1R 通路中的近端步骤仍然知之甚少，并且关于酪氨酸磷酸化在 IL-1R 信号传导中的重要性存在相互矛盾的证据。我们通过检查 IL-1 共刺激 Lek 缺陷的 Th2 细胞激活的能力解决了这个问题。我们的数据表明，在 Lck 缺失的情况下，尽管 IL-1RI 的表达水平正常，但 IL-1 共刺激途径仍被阻断。此外，该阻断与 I kappaB-α 的降解缺陷和 NF-kappaB 异二聚复合物的不完全激活有关。 NF-kappaB 单体（包括 p50、p65 和 c-Rel）的蛋白质表达在野生型和 Lck 缺陷型 Th2 细胞克隆中是相同的。最后，我们证明，在正常 Th2 细胞中，IL-1 刺激会导致包括 Lek 本身在内的几种底物的酪氨酸磷酸化快速诱导。这些发现强烈表明，Lek 是 Th2 淋巴细胞 IL-1 共刺激通路中信号传导所必需的。
Src-protein tyrosine kinases are intimately involved in TCR-initiated signaling in T lymphocytes. One member of this family, Lek, is also involved in CD28-mediated costimulation in Th1 cells. In Th2 lymphocytes, the costimulatory signal can also be provided by the interaction of IL-1 with type I IL-1R (IL-IRI), culminating in the activation of NF-kappaB transcription factors. Proximal steps in the IL-1R pathway, however, remain poorly understood, and there is conflicting evidence as to the importance of tyrosine phosphorylation in IL-1R signaling. We have addressed this issue by examining the ability of IL-1 to costimulate the activation of Lek-deficient Th2 cells. Our data demonstrate that, in the absence of Lck, the IL-1 costimulatory pathway is blocked despite the expression of normal levels of IL-1RI. Moreover, the block is associated with a defective degradation of I kappaB-alpha and an incomplete activation of NF-kappaB heterodimeric complexes. Protein expression of NF-kappaB monomers, including p50, p65, and c-Rel, is equivalent in both wild-type and Lck-deficient Th2 cell clones. Finally, we demonstrate that, in normal Th2 cells, stimulation with IL-1 leads to a rapid induction in tyrosine phosphorylation of several substrates including Lek itself. These findings strongly suggest that Lek is required for signaling in the IL-1 costimulatory pathway in Th2 lymphocytes.