McKean D J, Bell M, Huntoon C, Rastogi S, Van Norstrand M, Podzorski R, Nilson A, Paya C
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Int Immunol. 1995 Jan;7(1):9-20. doi: 10.1093/intimm/7.1.9.
Previous studies have demonstrated that IL-1 receptor (IL-1R)- and TCR-initiated signals can interact synergistically to increase the rate of transcription of several lymphokine and lymphokine receptor genes during the competence phase of the activation program in T helper lymphocytes. In this report we describe how signals initiated through the type I IL-1R interact with signals from the antigen receptor to synergistically augment the transactivating properties of NF-kappa B. The synergistic antigen receptor initiated signals are mediated through protein kinase C because they can be mimicked by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, but not with calcium ionophores; and are staurosporine sensitive but cyclosporine resistant. Gel shift analyses demonstrate that NF-kappa B nuclear translocation is stimulated primarily by IL-1 rather than by antigen receptor signals. Western blot and phosphorylation analyses demonstrate that the synergistic effect on NF-kappa B functional activity is independent of I kappa B alpha (MAD3)-NF-kappa B dissociation in the cytosol and is not associated with I kappa B nuclear translocation. The IL-1-induced NF-kappa B DNA nuclear localization is transient and can be prolonged either by an antigen receptor-initiated signal or by inhibiting protein synthesis. These results suggest that IL-1 induces both NF-kappa B nuclear translocation and the synthesis of a protein(s) responsible for terminating NF-kappa B-DNA interaction in the nucleus. Antigen receptor signals prolong NF-kappa B-DNA interaction, probably by functionally antagonizing the IL-1-induced synthesis of a protein(s) responsible for the transient NF-kappa B-DNA interaction and consequently synergistically enhance IL-1-induced NF-kappa B-dependent gene transcription.
先前的研究表明，在T辅助淋巴细胞激活程序的感受态阶段，白细胞介素-1受体（IL-1R）和T细胞受体（TCR）启动的信号可协同相互作用，以提高几种淋巴因子和淋巴因子受体基因的转录速率。在本报告中，我们描述了通过I型IL-1R启动的信号如何与抗原受体的信号相互作用，以协同增强核因子-κB（NF-κB）的反式激活特性。协同的抗原受体启动信号是通过蛋白激酶C介导的，因为它们可被佛波酯12-O-十四酰佛波醇-13-乙酸酯模拟，但不能被钙离子载体模拟；并且对星形孢菌素敏感，但对环孢素耐药。凝胶迁移分析表明，NF-κB的核转位主要受IL-1刺激，而非抗原受体信号。蛋白质印迹和磷酸化分析表明，对NF-κB功能活性的协同作用独立于胞质溶胶中IκBα（MAD3）-NF-κB的解离，且与IκB的核转位无关。IL-1诱导的NF-κB DNA核定位是短暂的，可通过抗原受体启动的信号或抑制蛋白质合成来延长。这些结果表明，IL-1诱导NF-κB核转位以及负责终止细胞核中NF-κB-DNA相互作用的一种或多种蛋白质的合成。抗原受体信号可能通过在功能上拮抗IL-1诱导的负责短暂NF-κB-DNA相互作用的一种或多种蛋白质的合成，从而延长NF-κB-DNA相互作用，并因此协同增强IL-1诱导的NF-κB依赖性基因转录。
