Sarasin-Filipowicz, Magdalena. Interferon signaling in chronic hepatitis C : mechanisms and implications for therapy. 2008, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_8508
In the second approach we addressed the mechanisms underlying the pre-activation of the
endogenous IFN system in a defined group of HCV patients (future non-responders). For this
purpose, we analyzed ISG expression by quantitative RT-PCR and nuclear localization of
STAT1 by immunohistochemistry in a cohort of 112 patients with CHC. By subdividing this
cohort according to the HCV genotype (GT), we discovered that patients infected with HCV
GT 1 and 4 more often show hepatic ISG preactivation than GT 2 and 3 patients, thus
providing an explanation for the poor response to IFN therapy seen in GT 1/4 patients. We
analyzed the possible involvement of viral sensory pathways in type I IFN production and
ISG upregulation. Previously, the viral HCV NS3-4A protease was shown to interfere with
viral sensory pathways by cleaving and thereby inactivating an important adaptor molecule,
Cardif. We therefore assessed Cardif cleavage in liver biopsies of HCV patients and found
that cleavage more often occurred in patients infected with HCV GTs 2 and 3. Our findings
support a concept that the success of the virus in preventing the induction of the endogenous
IFN system in the livers of these patients would, however, come at the cost of being more
susceptible to IFNα therapies as is the case with GT 2/3 patients.
In the third approach we designed an experimental model to study the molecular basis of
refractoriness of IFN signaling in vivo. Previously, cell culture experiments demonstrated a
long lasting desensitization period, which followed the initial activation of the IFNα
signaling pathway. In the approach used here, we established a mouse model in which
continuous presence of IFNα in vivo was achieved by multiple subcutaneous injections,
mimicking the constitutively high serum levels achieved by pegIFNα in patients.
Interestingly, this resulted in refractoriness of IFNα signaling. Activation of STAT1 and
STAT2, but not STAT3, in the mouse liver was desensitized by continuous IFNα stimulation.
To elucidate the mechanism of this refractoriness, the role of negative regulators of the Jak-
STAT signaling pathway was investigated. IFN signaling remained refractory in mice
deficient in suppressor of cytokine signaling (SOCS) 3 and persisting refractoriness was also
observed in mice deficient in IL-10, a strong inducer of SOCS3. Ubiquitin specific peptidase
18 (USP18/UBP43) was recently identified as novel negative regulator of IFNα signal
transduction. Interestingly, refractoriness could be overcome in USP18/UBP43 knockout
mice. These data strongly indicate that UBP43 is the decisive factor in inducing a refractory
state in the IFNα signaling pathway in vivo.
|Advisors:||Heim, Markus Hermann|
|Committee Members:||Palmer, Ed|
|Faculties and Departments:||03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Gastroenterologie|
|Bibsysno:||Link to catalogue|
|Number of Pages:||125|
|Last Modified:||30 Jun 2016 10:41|
|Deposited On:||13 Feb 2009 16:49|
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