Trincucci, Gaia. Interferon signaling in viral hepatitis. 2013, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10370
In the first part of the thesis the role of unphosphorylated-STAT1 (U-STAT1) in mediating the up-regulation of hepatic IRGs in CHC patients was investigated. We have reported that STAT1 accumulates in the liver of CHC patients non-responders. Furthermore, experimental evidences suggest that STAT1 could play a role as transcription factor independently by its phosphorylation on tyrosine 701 and its unphosphorylated form can drive the expression of a subset of IRGs. In the present study we took advantage of a cell line constitutively lacking STAT1 expression and we exogenously re-expressed a mutant form of STAT1 that can not be phosphorylated, mimicking U-STAT1. We proved that U-STAT1 per se is not able to induce the expression of IRGs and it is unlikely to be the cause of the pre-activated IFN system observed in the liver of non-responders CHC patients.
In the second part of the thesis, we investigated the role of IFN?s signaling pathway in the definition of the pre-activated hepatic IFN system in CHC. IFN?s are the most recently group of IFNs. IFN?s signal through the cells via a different receptor compared to the one of IFN?. However, the intracellular signaling pathway of the two class of cytokines is completely overlapping, leading to the up-regulation of the same IRGs. We demonstrated that in an hepatoma cell line Huh7 the over-expression of IL28R?, one of the two chains of INF? receptor complex, mediates the long lasting up-regulation of IRGs upon IFN? stimulation. We confirmed our results in human liver biopsies, where we found a significant positive correlation between IL28R? and IRGs expression. We observed that IL28R? is an IRG itself but its level of expression is modulated by allelic variants at SNPs mapping in the IL28B locus, that have been associated to treatment response in CHC patients.
In conclusion we provide evidences of a molecular mechanism that links the pre-activation of the hepatic IFN system (and non-response) and allelic variants at IL28B locus.
|Committee Members:||Handschin, Christoph|
|Faculties and Departments:||03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Hepatologie > Hepatologie (Heim)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||102 S.|
|Last Modified:||30 Jun 2016 10:52|
|Deposited On:||03 May 2013 14:50|
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