Abstract
BackgroundType-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 FindingsWe 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/SignificanceOur 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.
Highlights
The interferons (IFNs) are a family of cytokines [1,2]
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
In contrast to our expectations [35], we detected two AIM2 protein bands in B lymphocytes, which migrated close to each other. It is not clear whether the slow-migrating protein band that was detected by the AIM2-specific antibody is a modified form of the AIM2 protein or an alternatively spliced isoform [15]
Summary
The interferons (IFNs) are a family of cytokines [1,2]. The family includes type-I (IFN-a and b), type-II (IFN-c), and type III IFNs [1,3]. IFNs exert multiple biological effects on cells through binding to cell surface receptor and activating the IFN-signaling [1]. The binding of the type I IFNs (a and b) to the cell surface receptor results in activating phosphorylation of signal transducer and activator of transcription 1 (STAT1) protein in the cytoplasm, which translocates to the nucleus and activates the transcription of the IFN-inducible genes, such as the IFI16 and AIM2 [4]. Most cell types produce low constitutive levels of type I IFNs [2]. Their expression is induced as a part of an innate immune response that is initiated after infections [1,2]. 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 typeI and type-II IFNs and explored whether the IFI16 protein could negatively regulate the activation of the AIM2 (or other) inflammasome
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