| First Author | Sarasin-Filipowicz M | Year | 2009 |
| Journal | Mol Cell Biol | Volume | 29 |
| Issue | 17 | Pages | 4841-51 |
| PubMed ID | 19564419 | Mgi Jnum | J:152613 |
| Mgi Id | MGI:4359316 | Doi | 10.1128/MCB.00224-09 |
| Citation | Sarasin-Filipowicz M, et al. (2009) Alpha interferon induces long-lasting refractoriness of JAK-STAT signaling in the mouse liver through induction of USP18/UBP43. Mol Cell Biol 29(17):4841-51 |
| abstractText | 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. |
