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

Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/2009; 29(17):4841-51. DOI: 10.1128/MCB.00224-09
Source: PubMed


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.

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Available from: Dong-Er Zhang, Aug 27, 2014
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    • "IFNL3 on the other hand upregulated USP18 and SOCS1 over 24 h (USP 18: 13.6- to 19.6-fold; SOCS1: 3.3- to 6.8-fold).114 USP18 was shown to be necessary and sufficient to induce differential desensitization by impairing JAK1 at the IFNAR.117,118,119 Although these expression profiles may be cell type-specific, the potent and sustained effects of USP18 upregulation in the context of a chronic infection may significantly affect IFN-α induced signaling. "
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    ABSTRACT: Type-III interferons (IFN-λ, IFNL) are the most recently described family of IFNs. This family of innate cytokines are increasingly being ascribed pivotal roles in host–pathogen interactions. Herein, we will review the accumulating evidence detailing the immune biology of IFNL during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. IFNLs exert antiviral effects via induction of IFN-stimulated genes. Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor α-subunit genes have been strongly associated with IFN-α-based treatment of chronic hepatitis C virus infection. The clinical impact of these SNPs may be dependent on the status of viral infection (acute or chronic) and the potential to develop viral resistance. Another important function of IFNLs is macrophage and dendritic cell polarization, which prime helper T-cell activation and proliferation. It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines. Therefore, can such SNPs affect the IFNL signaling and thereby modulate the Th1/Th2 balance during infection? In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response.
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    • "As alternative hypothesis, increased sCD14 in patients with worst liver disease and HCV genotype 1–4 might reflect heightened endogenous interferon (IFN) rather than increased MT. Indeed, HCV infection activates the endogenous IFN system in the liver [44]; yet such gene pre-activation is associated to the lack of response to IFN-alpha/ribavirin, possibly through a refractory state to IFN-mediated signalling [45]–[48]. Patients harbouring HCV genotypes 1–4 have a higher likelihood of failing EVR/SVR and have higher levels of endogenous IFN and IFN-stimulated gene (ISG) expression [18], [49]. Given that the exposure to IFN has been shown to transiently activate macrophages with sCD14 release [50], and that CD14+ monocytes of HIV-infected patients display higher ISG expression [51], our data that patients with cirrhosis, 1–4 genotypes and non-responders show increased sCD14 despite equal plasma LPS, allow to hypothesise in these individuals an overall higher innate immune activation with higher endogenous IFN, that results in sCD14 release, while rendering the cells less sensitive to exogenous IFN. "
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    ABSTRACT: Microbial translocation (MT) through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and immune activation may hamper anti-HCV response in HIV/HCV patients. 98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha)/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS), host response to MT (sCD14), CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log(10) reduction from baseline after 12 weeks of therapy) and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy). Mann-Whitney/Chi-square test and Pearson's correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR. 71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1-4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2-3 (p = 0.053) and no cirrhosis (p = 0.052). EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively), but similar T-cell activation compared to Non-EVR (Null Responders, NR) and Non-SVR (N-SVR) subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031-0.688, p = 0.015). SVR was associated only with HCV genotypes 2-3 (AOR 0.022 for genotypes 1-4 vs 2-3, 95%CI 0.001-0.469, p = 0.014). In HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy.
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    • "The pleiotropic activities of IFNs must be tightly down regulated in time and space and several mechanisms have been shown to co-exist in order to attenuate IFN-initiated Jak/Stat signaling (reviewed in [9]). In an in vivo model, Sarasin et al showed that liver cells from mice repeatedly injected with murine IFN α become refractory to further IFN α stimulation [10]. The ISG-encoded isopeptidase USP18/Ubp43 was found to be essential for the establishment of the desensitized state [10], [11]. "
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