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Title: Cytokine regulation of heat shock protein 90 gene expression with reference to systemic lupus erythematosus
Author: McNab, Deborah Mary
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2001
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Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterised by the presence of a wide range of autoantibodies. A subset of SLE patients have autoantibodies against the 90 kDa heat shock protein (hsp90.) This protein is overexpressed in the peripheral blood mononuclear cells (PBMCs) SLE patients from this group as compared to healthy controls. Hsp90 is a cytoplasmic protein that acts as a chaperone, and has two isoforms alpha and beta, which are products of separate genes. The elevated level of hsp90 in SLE correlates with increased expression of the beta isoform. The enhanced level of protein within the cell may cause surface expression of the molecule, thus making it a target for the immune system. The cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10) are reported to be elevated in the serum of SLE patients in comparison to healthy controls, and correlate with disease activity. In murine lupus models the use of anti-IL-6 and anti-IL-10 therapy has relieved the symptoms of the disease and prolonged life. IL-6 and IL-10 can activate the expression of the hsp90β gene in both liver cells and PBMCs. In the IL-6 overexpressing transgenic mouse the increased concentrations of the cytokine led to elevated levels of hsp90 and autoantibodies against this protein. This suggests that IL-6 may have a role in the pathogenesis of SLE. This investigation initially looked at the differences in the expression of the two hsp90 isoforms in response to cytokines, to try and identify why only the beta form is elevated in SLE patients. Constructs of the promoter region of each hsp90 gene upstream of the Chloramphenicol Acetyl Transferase reporter gene were obtained. A hepatic cell line was used to measure protein levels and CAT activity of each hsp90 isoform upon exposure to cytokine and heat shock. IL-6, IL-10 and IFN activated the beta promotery. However hsp90a was only activated by IL-6 and IL-10, not IFNγ. These results suggest that the differences seen in the SLE patients maybe due to elevated levels of IFNγ. Previous investigations into the correlation between IL-6 or IL-10 and disease activity in SLE have used an overall disease activity index. The British Isles Lupus Assessment Group system records the severity of disease in each of eight categories, from which a global score can be derived. The plasma levels of IFNγ, IL6 and IL-10 in SLE patients were measured by ELISA to identify any relationship with disease activity in each BILAG category. Elevated levels of IL-6 were detected in 52% patients, and 16% patients had increased levels of IL-10. Elevated levels of IFNy were not detected. The concentration of IL-6 correlated with the global score and levels of hsp90. There were no other significant correlations between cytokine levels and disease activity. The increased levels of IL-6 seen in the plasma of SLE patients correlated well with the hsp90 content of PBMCs from the same patients. This suggests that elevated IL-6 causes increased transcription of hsp90. IL-6 induced the expression of both isoforms of hsp90 in vitro. Therefore correlation between hsp90 protein levels and the transcription of the beta isoform reported previously may be due to a greater abundance of the beta form.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available