Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43

Mol Cell Biol. 2009 Sep;29(17):4841-51. doi: 10.1128/MCB.00224-09. Epub 2009 Jun 29.

Abstract

Recombinant alpha interferon (IFN-alpha) is used for the treatment of viral hepatitis and some forms of cancer. During these therapies IFN-alpha is injected once daily or every second day for several months. Recently, the long-acting pegylated IFN-alpha (pegIFN-alpha) has replaced standard IFN-alpha in therapies of chronic hepatitis C because it is more effective, supposedly by inducing a long-lasting activation of IFN signaling pathways. IFN signaling in cultured cells, however, becomes refractory within hours, and little is known about the pharmacodynamic effects of continuously high IFN-alpha serum concentrations. To investigate the behavior of the IFN system in vivo, we repeatedly injected mice with IFN-alpha and analyzed its effects in the liver. Within hours after the first injection, IFN-alpha signaling became refractory to further stimulation. The negative regulator SOCS1 was rapidly upregulated and likely responsible for early termination of IFN-alpha signaling. For long-lasting refractoriness, neither SOCS1 nor SOCS3 were instrumental. Instead, we identified the inhibitor USP18/UBP43 as the key mediator. Our results indicate that the current therapeutic practice using long-lasting pegIFN-alpha is not well adapted to the intrinsic properties of the IFN system. Targeting USP18 expression may allow to exploit the full therapeutic potential of recombinant IFN-alpha.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Humans
  • Interferon Type I / pharmacology*
  • Interleukin-10 / metabolism
  • Janus Kinases / genetics
  • Janus Kinases / metabolism*
  • Liver* / drug effects
  • Liver* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Recombinant Proteins
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism*
  • Signal Transduction / drug effects*
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Ubiquitin Thiolesterase

Substances

  • Interferon Type I
  • Recombinant Proteins
  • STAT Transcription Factors
  • Socs1 protein, mouse
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Interleukin-10
  • Janus Kinases
  • Endopeptidases
  • Usp18 protein, mouse
  • Ubiquitin Thiolesterase