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Title: IFNγ-mediated apoptosis in the primary hepatocyte
Author: McCullough, Christian Thomas
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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This thesis describes the establishment of a primary cell culture system to investigate IFN-γ-induced hepatocyte apoptosis. We hypothesised that the hepatocyte response to IFN signalling is context-dependent, influenced by both external stimuli, such as growth factors, and the internal state of the cell. This was tested using a dual approach; firstly to assess the importance of known genes, IRF-l, p53 and p21 on apoptosis in this system and the contribution of known apoptotic inducers, such as CD95 and c-myc, to IFN-γ signalling. Secondly, to assess the feasibility of a functional gene trap assay in primary cells to identify unknown effectors of IFNγ-induced apoptosis. The results show that IFNΔ induces primary hepatocyte apoptosis in the context of serum- deprivation, an effect requiring IRF-1 but not p53. A deficiency of p21 potentiated apoptosis. Rather than generating a single outcome, the cellular response to IFNγ is modulated by external factors. IFNγ-induced apoptosis was inhibited by specific cytokines, while IFNγ potentiated primary hepatocyte apoptosis induced by death receptor signalling and DNA damage, in an IRF-1-dependent manner. Further, thyroid hormone potentiated IFNγ-induced apoptosis via MAPK- mediated phosphorylation of STAT1 at serine 727. This occurred via an extra-nuclear, that is non-genomic, signalling pathway. For the first time in primary hepatocytes it is demonstrated that IFNγ-mediated apoptotic signalling required the cell surface interaction of CD95 and its ligand and that IFNγ induces soluble CD95 ligand release from hepatocyte monolayers. The characteristics of IFNγ-mediated apoptosis identified in this research led to a hypothesis that c-myc contributes to IFNγ-induced apoptosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available