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Molecular and Cellular Biology, September 2009, p. 4841-4851, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00224-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Alpha Interferon Induces Long-Lasting Refractoriness of JAK-STAT Signaling in the Mouse Liver through Induction of USP18/UBP43{triangledown}

Magdalena Sarasin-Filipowicz,1,2,{dagger} Xueya Wang,1,{dagger} Ming Yan,3 Francois H. T. Duong,1 Valeria Poli,4 Douglas J. Hilton,5 Dong-Er Zhang,3 and Markus H. Heim1,2*

Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland,1 Division of Gastroenterology and Hepatology, University Hospital Basel, CH-4031 Basel, Switzerland,2 Moores UCSD Cancer Center, Department of Pathology and Division of Biological Sciences, University of California San Diego, La Jolla, California 92093,3 Department of Genetics, Biology and Biochemistry, University of Turin, 10126 Turin, Italy,4 Division of Molecular Medicine, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia5

Received 19 February 2009/ Returned for modification 15 March 2009/ Accepted 18 June 2009

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}.

* Corresponding author. Mailing address: Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. Phone: 41 61 265 33 62. Fax: 41 61 265 23 50. E-mail: markus.heim{at}unibas.ch

{triangledown} Published ahead of print on 29 June 2009.

{dagger} M.S.-F. and X.W. contributed equally to this study.

Molecular and Cellular Biology, September 2009, p. 4841-4851, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.00224-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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