title: IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors: Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors: Sudhakar
authors: S
authors: Veeranki
authors: Xin
authors: X
authors: Duan
authors: Ravichandran
authors: R
authors: Panchanathan
authors: Hongzhu
authors: H
authors: Liu
authors: Divaker
authors: D
authors: Choubey
mesh_terms: D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D002460:Cell Line; D004268:DNA-Binding Proteins; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000276:immunology*; D010750:Phosphoproteins / Q000276:immunology*
chemical_list: C410167:AIM2 protein, human; D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D007370:Interferon Type I; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; C076700:IFI16 protein, human; D020170:Caspase 1