IFI16 蛋白通过抑制炎症小体激活半胱天冬酶-1来介导 I 型干扰素的抗炎作用。
IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes.
机构信息
Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, United States of America.
出版信息
PLoS One. 2011;6(10):e27040. doi: 10.1371/journal.pone.0027040. Epub 2011 Oct 28.
BACKGROUND
Type-I interferons (IFNs) are used to treat certain inflammatory diseases. Moreover, activation of type-I IFN-signaling in immune cells inhibits the production of proinflammatory cytokines and activation of inflammasomes. However, the molecular mechanisms remain largely unknown. Upon sensing cytosolic double-stranded DNA, the AIM2 protein forms the AIM2-ASC inflammasome, resulting in activation of caspase-1. Given that the IFI16 and AIM2 proteins are IFN-inducible and can heterodimerize with each other, we investigated the regulation of IFI16, AIM2, and inflammasome proteins by type-I and type-II IFNs and explored whether the IFI16 protein could negatively regulate the activation of the AIM2 (or other) inflammasome.
METHODOLOGY/ PRINCIPAL FINDINGS: We found that basal levels of the IFI16 and AIM2 proteins were relatively low in peripheral blood monocytes (CD14(+)) and in the THP-1 monocytic cell line. However, treatment of THP-1 cells with type-I (IFN-α or β) or type-II (IFN-γ) IFN induced the expression levels of IFI16, AIM2, ASC and CASP1 proteins. The induced levels of IFI16 and AIM2 proteins were detected primarily in the cytoplasm. Accordingly, relatively more IFI16 protein bound with the AIM2 protein in the cytoplasmic fraction. Notably, increased expression of IFI16 protein in transfected HEK-293 cells inhibited activation of caspase-1 by the AIM2-ASC inflammasome. Moreover, the constitutive knockdown of the IFI16 expression in THP-1 cells increased the basal and induced [induced by poly(dA:dT) or alum] activation of the caspase-1 by the AIM2 and NLRP3 inflammasomes.
CONCLUSIONS/SIGNIFICANCE: Our observations revealed that the type-I and type-II IFNs induce the expression of IFI16, AIM2, and inflammasome proteins to various extents in THP-1 cells and the expression of IFI16 protein in THP-1 cells suppresses the activation of caspase-1 by the AIM2 and NLRP3 inflammasomes. Thus, our observations identify the IFI16 protein as a mediator of the anti-inflammatory actions of the type-I IFNs.
背景
I 型干扰素（IFNs）用于治疗某些炎症性疾病。此外，免疫细胞中 I 型 IFN 信号的激活抑制前炎性细胞因子的产生和炎性小体的激活。然而，分子机制在很大程度上仍是未知的。在检测到细胞质中的双链 DNA 后，AIM2 蛋白形成 AIM2-ASC 炎性小体，导致 caspase-1 的激活。鉴于 IFI16 和 AIM2 蛋白是 IFN 诱导的，可以相互异二聚化，我们研究了 I 型和 II 型 IFN 对 IFI16、AIM2 和炎性小体蛋白的调节作用，并探讨了 IFI16 蛋白是否能负调节 AIM2（或其他）炎性小体的激活。
方法/主要发现：我们发现外周血单核细胞（CD14(+)）和 THP-1 单核细胞系中 IFI16 和 AIM2 蛋白的基础水平相对较低。然而，I 型（IFN-α 或 β）或 II 型（IFN-γ）IFN 处理 THP-1 细胞诱导 IFI16、AIM2、ASC 和 CASP1 蛋白的表达水平。IFI16 和 AIM2 蛋白的诱导水平主要在细胞质中检测到。因此，在细胞质部分中相对更多的 IFI16 蛋白与 AIM2 蛋白结合。值得注意的是，转染的 HEK-293 细胞中 IFI16 蛋白表达的增加抑制了由 AIM2-ASC 炎性小体引起的 caspase-1 的激活。此外，THP-1 细胞中 IFI16 表达的组成性敲低增加了由 AIM2 和 NLRP3 炎性小体引起的 caspase-1 的基础和诱导（由 poly(dA:dT) 或 alum 诱导）激活。
结论/意义：我们的观察结果表明，I 型和 II 型 IFNs 在 THP-1 细胞中以不同程度诱导 IFI16、AIM2 和炎性小体蛋白的表达，并且 THP-1 细胞中 IFI16 蛋白的表达抑制了由 AIM2 和 NLRP3 炎性小体引起的 caspase-1 的激活。因此，我们的观察结果确定 IFI16 蛋白是 I 型 IFN 的抗炎作用的介导物。
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