期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 29, 期 17, 页码 4841-4851出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00224-09
关键词
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资金
- Swiss National Science foundation [320000-116106]
- Swiss Cancer League [KLS-01832-02-2006]
- Krebsliga Basel [8/05]
- National Institutes of Health [HL091549]
- Roche Research Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL091549] Funding Source: NIH RePORTER
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.
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