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

Abstract

Recombinant alpha interferon (IFN-␣) is used for the treatment of viral hepatitis and some forms of cancer. During these therapies IFN-␣ is injected once daily or every second day for several months. Recently, the long-acting pegylated IFN-␣ (pegIFN-␣) has replaced standard IFN-␣ 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-␣ serum concentrations. To investigate the behavior of the IFN system in vivo, we repeatedly injected mice with IFN-␣ and analyzed its effects in the liver. Within hours after the first injection, IFN-␣ signaling became refractory to further stimulation. The negative regulator SOCS1 was rapidly upregulated and likely responsible for early termination of IFN-␣ 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-␣ 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-␣.

Homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial

“…5,6,29 However, although SOCS-3 has been reportedly elevated in the liver of chronic hepatitis C patients with IR, 7 its role in reducing the response to therapy has been challenged by experimental 30 and clinical data. 31 A second hypothesis is based on data suggesting that high concentrations of insulin directly inhibit interferon alpha signaling, independently of SOCS-3.…”

IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18

“…USP18 has been reported to be responsible for the persistent IFN-induced refractory mechanism that occurs following JAK-STAT signalling in mouse and human hepatocytes (Francois-Newton et al, 2011;Sarasin-Filipowicz et al, 2009). The microarray data showed that IFN-l4 induced strong USP18 expression (Fig.…”

“…Ubiquitin specific peptidase 18 (USP18), also known as ubiquitin-specific protease 43 (UBP43), provides strong negative feedback in the activation of the JAK-STAT pathway by binding to IFNAR2 (Sarasin-Filipowicz et al, 2009). USP18 has been reported to be responsible for the persistent IFN-induced refractory mechanism that occurs following JAK-STAT signalling in mouse and human hepatocytes (Francois-Newton et al, 2011;Sarasin-Filipowicz et al, 2009).…”

Expression characterization, genomic structure and function analysis of fish ubiquitin-specific protease 18 (USP18) genes

“…Therefore, host cells develop stringent mechanisms of signal attenuation, for example, termination of IFN signaling, to ensure an appropriate IFN response (Ivashkiv and Donlin, 2014;Schneider et al, 2014). Among the inhibitors, USP18 (ubiquitinspecific protease) impedes the expression of IFN-induced downstream genes by negative regulation of Jak-Stat signaling pathway Malakhova et al, 2003;Sarasin-Filipowicz et al, 2009;Schneider et al, 2014).…”

“…Indeed USP18-deleted mice are hypersensitive to IFN treatment and show enhanced resistance to viral infection (Malakhova et al, 2003;Ritchie and Zhang, 2004); USP18−/− cells treated with type I IFNs have enhanced and prolonged STAT1 phosphorylation, increased the expression of ISG (Malakhova et al, 2003;Murray et al, 2011;Sarasin-Filipowicz et al, 2009). Interestingly, USP18 is a major ISG15-specific protease for maintaining a proper balance of ISG15-conjugated proteins in cells; however, the antiviral roles of USP18 are independent of its ISG15 isopeptidase activity Malakhova et al, 2006;Osiak et al, 2005), and seem to be mediated by specific binding of USP18 to the IFN receptor IFNAR2 and subsequently disrupting IFNAR2-JAK1 interaction, thus negatively regulating IFN signaling cascade (Malakhova et al, 2006).…”