Alpha Interferon Induces Long-Lasting Refractoriness of JAK-STAT Signaling in the Mouse Liver through Induction of USP18/UBP43
- Sarasin-Filipowicz, Magdalena Division of Gastroenterology and Hepatology, University Hospital Basel, CH-4031 Basel, Switzerland
- Wang, Xueya Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland
- Yan, Ming Moores UCSD Cancer Center, Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California 92093
- Duong, Francois H. T. Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland
- Poli, Valeria Department of Genetics, Biology and Biochemistry, University of Turin, 10126 Turin, Italy
- Hilton, Douglas J. Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
- Zhang, Dong-Er Moores UCSD Cancer Center, Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California 92093
- Heim, Markus H. Division of Gastroenterology and Hepatology, University Hospital Basel, CH-4031 Basel, Switzerland
Published in:
- Molecular and Cellular Biology. - American Society for Microbiology. - 2009, vol. 29, no. 17, p. 4841-4851
English
ABSTRACT
Recombinant alpha interferon (IFN-α) is used for the treatment of viral hepatitis and some forms of cancer. During these therapies IFN-α is injected once daily or every second day for several months. Recently, the long-acting pegylated IFN-α (pegIFN-α) has replaced standard IFN-α 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-α serum concentrations. To investigate the behavior of the IFN system in vivo, we repeatedly injected mice with IFN-α and analyzed its effects in the liver. Within hours after the first injection, IFN-α signaling became refractory to further stimulation. The negative regulator SOCS1 was rapidly upregulated and likely responsible for early termination of IFN-α 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-α 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-α.
- Language
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- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1128/mcb.00224-09
- ISSN 0270-7306
- Persistent URL
- https://sonar.ch/global/documents/10943
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