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

作者：Sarasin Filipowicz Magdalena; Wang Xueya; Yan Ming; Duong Francois H T; Poli Valeria; Hilton Douglas J; Zhang Dong Er; Heim Markus H^*

来源：Molecular and Cellular Biology, 2009, 29(17): 4841-4851.

DOI：10.1128/MCB.00224-09

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.

• 出版日期2009-9-1
• 单位河北医科大学