Use this URL to cite or link to this record in EThOS:
Title: A study of the murine and human homologues of the natural resistance associated macrophage protein 1
Author: Goswami, T.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2000
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
To investigate the possibility that apoptotic cell death is a mechanism by which Nramp1 mediates resistance to macrophage infection, the influence of Nramp1 on cellular apoptosis was studied by DNA fragmentation analyses using the Nramp1WT and Nramp1M macrophage cell lines. It was observed that basal levels of apoptosis were higher in Nramp1WT cells than Nramp1M macrophages. The effect of activation with LPS and/or IFNγ on apoptosis appeared to be Nramp1-independent. Experiments with the iNOS specific inhibitor, SMT, and the NO donor, sodium nitroprusside, demonstrated that NO, particularly in LPS activated cells, induced increased apoptotic cell death in Nramp1WT macrophages compared to Nramp1M cells. Studies with the superoxide scavenger DMTU further showed that superoxide enhanced apoptosis in activated macrophages and that its effects were more pronounced in Nramp1WT cells. It was demonstrated that cellular iron levels significantly influenced apoptotic cell death, iron depletion being associated with enhanced apoptosis in Nramp1WT cells an conversely, reduced cell death in NrampWT/RAW264.7 cells. Comparison of these cumulative data with subsequent experiments using human macrophages cell lines (THP1 and U937) expressing full length human NRAMP1 demonstrated that the phenotype of the latter cells with respect to apoptosis is similar to that of Nramp1WT macrophages. Apoptotic responses were more pronounced in the developmentally mature THP1 monocytic cell line, expressing higher levels of inducible NRAMP1, than in the U937 macrophage cell line with lower levels of NRAMP1 expression. These data in summation strongly support a relationship between Nramp1/NRAMP1 and apoptosis and also point out the importance of some of the intermediate effector molecules of this process.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available