Innate Immunity in Pluripotent Human Cells ATTENUATED RESPONSE TO INTERFERON-β
Innate Immunity in Pluripotent Human Cells ATTENUATED RESPONSE TO INTERFERON-β
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DOI：
10.1074/jbc.m112.435461
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发表时间：
2013-05-31
影响因子：
4.8
通讯作者：
Carmichael, Gordon G.
中科院分区：
文献类型：
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作者：
Hong, Xiao-Xiao;Carmichael, Gordon G.
I 型干扰素 (IFN-α/β) 与细胞表面受体 IFNAR1 和 IFNAR2 结合，触发信号级联反应，导致数百个 IFN 刺激基因的转录。这种反应是先天免疫的重要组成部分，因为它在细胞中建立“抗病毒状态”并保护它们免受进一步的损害。先前的研究表明，与分化的细胞相比，多能人类细胞对细胞质双链RNA（dsRNA）的反应要弱得多，并且只能产生最少量的IFN-β。我们在此表明，人胚胎干细胞 (hESC) 和人诱导多能干细胞 (hiPSC) 也表现出对 IFN-β 的减弱反应。尽管所有已知的 I 型 IFN 信号传导成分均在这些细胞中表达，但 STAT1 磷酸化在 IFN-β 治疗后大大减弱。这种减弱的反应与细胞因子信号传导抑制因子 1 (SOCS1) 的高表达相关。 hESC 分化为滋养层细胞后，细胞获得了对 IFN-β 作出反应的能力，同时伴随着 STAT1 磷酸化的显着诱导以及 SOCS1 表达的减少。此外，hiPSC 中 SOCS1 的敲低增强了它们对 IFN-β 的反应能力。综上所述，我们的结果表明，对 I 型 IFN 的细胞反应减弱可能是多能人类细胞的普遍特征，并且这与 SOCS1 的高表达有关。
Type I interferon (IFN-alpha/beta) binds to cell surface receptors IFNAR1 and IFNAR2 and triggers a signaling cascade that leads to the transcription of hundreds of IFN-stimulated genes. This response is a crucial component in innate immunity in that it establishes an "antiviral state" in cells and protects them against further damage. Previous work demonstrated that, compared with their differentiated counterparts, pluripotent human cells have a much weaker response to cytoplasmic double-stranded RNA(dsRNA) and are only able to produce a minimal amount of IFN-beta. Weshow here that human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) also exhibit an attenuated response to IFN-beta. Even though all known type I IFN signaling components are expressed in these cells, STAT1 phosphorylation is greatly diminished upon IFN-beta treatment. This attenuated response correlates with a high expression of suppressor of cytokine signaling 1 (SOCS1). Upon differentiation of hESCs into trophoblasts, cells acquire the ability to respond to IFN-beta, and this is accompanied by a significant induction of STAT1 phosphorylation as well as a decrease in SOCS1 expression. Furthermore, SOCS1 knockdown in hiPSCs enhances their ability to respond to IFN-beta. Taken together, our results suggest that an attenuated cellular response to type I IFNs may be a general feature of pluripotent human cells and that this is associated with high expression of SOCS1.