Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection

Immunology Section and Liver Diseases Branch, NIDDK, NIH, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
Journal of Clinical Investigation (Impact Factor: 13.77). 12/2006; 116(11):3006-14. DOI: 10.1172/JCI29832
Source: PubMed

ABSTRACT IFN-gamma is known as the initial and primary inducer of immunoproteasomes during viral infections. We now report that type I IFN induced the transcription and translation of immunoproteasome subunits, their incorporation into the proteasome complex, and the generation of an immunoproteasome-dependent CD8 T cell epitope in vitro and provide in vivo evidence that this mechanism occurs prior to IFN-gamma responses at the site of viral infection. Type I IFN-mediated generation of immunoproteasomes was initiated by either poly(I:C) or HCV RNA in human hepatoma cells and was inhibited by neutralization of type I IFN. In serial liver biopsies of chimpanzees with acute HCV infection, increases in immunoproteasome subunit mRNA preceded intrahepatic IFN-gamma responses by several weeks, instead coinciding with intrahepatic type I IFN responses. Thus, viral RNA-induced innate immune responses regulate the antigen-processing machinery, which occurs prior to the detection of IFN-gamma at the site of infection. This mechanism may contribute to the high effectiveness (95%) of type I IFN-based therapies if administered early during HCV infection.

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Available from: Peter-Michael Kloetzel, Aug 11, 2015
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    • "In line with the induction of ISGs by HCV infection itself enhanced transcription of ISGs in acutely and chronically HCV-infected chimpanzees as well as chronically infected patients has been observed. Importantly, the subsets of upregulated ISGs detected in vivo overlap to a large degree with those detected in IFN-treated cell cultures in in vitro [10] [11] [47] [48] [51] [67] [68] "
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    • "In addition, genes involved in antigen processing such as components of the immunoproteasome are expressed at higher levels. This is consistent with studies in chimpanzees, where virus induced type 1 interferons induced immunoproteasome units as well (Shin et al., 2006). On the anti-inflammatory side, genes like TRAIL and FAS were expressed at higher levels. "
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