Alpha Interferon Induces Long-Lasting Refractoriness of JAK-STAT Signaling in the Mouse Liver through Induction of USP18/UBP43
- Author(s)
- Sarasin-Filipowicz, M; Wang, XY; Yan, M; Duong, FHT; Poli, V; Hilton, DJ; Zhang, DE; Heim, MH;
- Details
- Publication Year 2009-09-01,Volume 29,Issue #17,Page 4841-4851
- Journal Title
- MOLECULAR AND CELLULAR BIOLOGY
- Publication Type
- Journal Article
- 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.
- Publisher
- AMER SOC MICROBIOLOGY
- Keywords
- CHRONIC HEPATITIS-C; UBP43 USP18; VIRAL-INFECTION; GENE ACTIVATION; VIRUS-INFECTION; INTERLEUKIN-10 RECEPTOR; PROTEIN ISGYLATION; INITIAL TREATMENT; PLUS RIBAVIRIN; IFN-ALPHA
- Publisher's Version
- https://doi.org/10.1128/MCB.00224-09
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2009-09-01 12:00:00