Min W, Pober J S, Johnson D R
Department of Pathology and the Molecular Cardiobiology Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Circ Res. 1998 Oct 19;83(8):815-23. doi: 10.1161/01.res.83.8.815.
Interferon (IFN)-gamma and IFN-alpha/beta induction of the transporter associated with antigen processing-1 (TAP1) promoter was compared in HeLa cells and endothelial cells (ECs). In HeLa cells, IFN-gamma acts through Stat1alpha/Stat1alpha homodimers binding to the gamma activating sequence (GAS) and IFN-alpha/beta acts through Stat1/Stat2/p48 binding to the IFN-stimulated response element (ISRE). In ECs, however, IFN-gamma and IFN-alpha/beta act through both the GAS and ISRE. The basis of the IFN signaling crossover in ECs was investigated. HeLa and ECs contain similar ratios of Stat1alpha to Stat2 proteins, and IFN-alpha/beta also activates the same Janus kinases (JAKs) (Jak1 and tyrosine kinase (Tyk) 2 but not Jak2). However, IFN-alpha/beta activates more Stat1alpha than does IFN-gamma in ECs, whereas the reverse occurs in HeLa, and expression of the IFN-alpha/beta receptor-associated phosphatase SHP-1 is much lower in ECs than HeLa cells. Overexpression of SHP-1 in ECs blocks IFN-alpha/beta signaling through GAS, and expression of a dominan negative SHP-1 in HeLa cells permits IFN-alpha/ss signaling through GAS, demonstrating a role for SHP-1 in regulating crossovers between the IFN-alpha/beta and IFN-gamma signaling pathways.
在HeLa细胞和内皮细胞（ECs）中比较了干扰素（IFN）-γ和IFN-α/β对与抗原加工相关的转运体1（TAP1）启动子的诱导作用。在HeLa细胞中，IFN-γ通过Stat1α/Stat1α同型二聚体与γ激活序列（GAS）结合发挥作用，而IFN-α/β通过Stat1/Stat2/p48与干扰素刺激反应元件（ISRE）结合发挥作用。然而，在ECs中，IFN-γ和IFN-α/β通过GAS和ISRE两者发挥作用。研究了ECs中IFN信号交叉的基础。HeLa细胞和ECs中Stat1α与Stat2蛋白的比例相似，并且IFN-α/β也激活相同的Janus激酶（JAKs）（Jak1和酪氨酸激酶（Tyk）2，但不激活Jak2）。然而，在ECs中，IFN-α/β比IFN-γ激活更多的Stat1α，而在HeLa细胞中情况相反，并且ECs中与IFN-α/β受体相关的磷酸酶SHP-1的表达远低于HeLa细胞。在ECs中过表达SHP-1可阻断通过GAS的IFN-α/β信号传导，而在HeLa细胞中表达显性负性SHP-1可使通过GAS的IFN-α/β信号传导，这表明SHP-1在调节IFN-α/β和IFN-γ信号通路之间的交叉中起作用。
