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Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection
Eui-Cheol Shin, … , Peter-M. Kloetzel, Barbara Rehermann
Eui-Cheol Shin, … , Peter-M. Kloetzel, Barbara Rehermann
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):3006-3014. https://doi.org/10.1172/JCI29832.
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Research Article Immunology

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

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Abstract

IFN-γ 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-γ 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-γ 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-γ 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.

Authors

Eui-Cheol Shin, Ulrike Seifert, Takanobu Kato, Charles M. Rice, Stephen M. Feinstone, Peter-M. Kloetzel, Barbara Rehermann

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Figure 6

Induction of immunoproteasome subunits in the liver precedes infiltration of CD8 T cells.

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Immunoproteasome subunit mRNA levels increase early in acute HCV infecti...
CD8β mRNA levels were quantified in serial liver biopsies of chimpanzees with acute HCV infection. CD8β mRNA amounts (squares) correlated closely with IFN-γ mRNA amounts (gray lines; values reproduced from Figure 5D for reference).

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