STAT-1α and IFN-γ as Modulators of TNF-α Signaling in Macrophages: Regulation and Functional Implications of the TNF Receptor 1:STAT-1α Complex1
STAT-1α and IFN-γ as Modulators of TNF-α Signaling in Macrophages: Regulation and Functional Implications of the TNF Receptor 1:STAT-1α Complex1
复制标题
STAT-1α 和 IFN-γ 作为巨噬细胞中 TNF-α 信号传导的调节剂：TNF 受体 1：STAT-1α 复合物的调节和功能意义
作者：
D. Wesemann;E. Benveniste
TNF-α和IFN-γ协同激活巨噬细胞。在IFN-γ存在下，NF-κB的TNF-α依赖性活化更强。在TNF-α处理的细胞中，STAT-1α与TNFR 1结合，这种结合减弱了TNF-α介导的NF-κB活化。我们假设，由于IFN-γ信号传导导致STAT-1α的核定位将阻止其被募集到TNFR 1，从而增强TNF-α诱导的NF-κB活化。在RAW264.7巨噬细胞系中，TNF-α处理确实将STAT-1α募集至TNFR 1，并且当细胞暴露于IFN-γ时，这种关联被废除。TNF-α处理诱导STAT-1α缺陷细胞中NF-κB更强的活化，STAT-1α的恢复抑制TNF-α依赖性NF-κB活化。我们的研究结果表明，在这两种细胞因子途径之间存在受体近端水平的串扰：IFN-γ通过从细胞质中耗尽STAT-1α来限制STAT-1α对TNFR 1的可用性，从而允许TNF-α连接后的最佳NF-κB活化。
TNF-α and IFN-γ cooperate in the activation of macrophages. TNF-α-dependent activation of NF-κB is stronger in the presence of IFN-γ. STAT-1α associates with TNFR1 in TNF-α-treated cells, and this association attenuates TNF-α-mediated NF-κB activation. We hypothesized that nuclear localization of STAT-1α due to IFN-γ signaling would preclude it from being recruited to the TNFR1 and therefore enhance TNF-α-induced NF-κB activation. In the RAW264.7 macrophage cell line, TNF-α treatment indeed recruits STAT-1α to the TNFR1, and this association is abrogated when cells are exposed to IFN-γ. TNF-α treatment induces a more robust activation of NF-κB in STAT-1α-deficient cells, and restoration of STAT-1α inhibits TNF-α-dependent NF-κB activation. Our results suggest that a receptor-proximal level of cross-talk exists between these two cytokine pathways: IFN-γ limits STAT-1α availability to the TNFR1 by depleting STAT-1α from the cytoplasm, thus allowing for optimal NF-κB activation upon TNF-α ligation.
影响因子：
4.4
作者：
D. Guo;J. Dunbar;Chuanhe Yang;L. Pfeffer;D. Donner
通讯作者：
D. Guo;J. Dunbar;Chuanhe Yang;L. Pfeffer;D. Donner