Ripley, Barry James Marc; (2003) Cytokines and the regulation of heat shock proteins in systemic lupus erythematosus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Previous studies have reported elevated levels of the 90 kDa heat shock protein (Hsp 90) and autoantibodies to Hsp 90 in a subset of patients with systemic lupus erythematosus (SLE). However, the mechanisms leading to the overexpression of Hsp 90 in SLE and a link between this event and the induction of Hsp 90 autoantibodies, have remained unclear. Recent studies have shown that the cytokine IL-6, which is elevated in SLE, activates Hsp 90 gene expression in cultured cells via specific transcription factors, that include STAT-3. In view of the known role of STAT proteins in signalling pathways of the cytokine IL-10, the effect of IL-10 on Hsp 90 levels in different cells was investigated. IL-10 enhanced the expression of Hsp 90 in cultured cells. In reporter gene assays, IL-10 activated both the Hsp 90α and Hsp 90β promoters directly. Activation of the Hsp 90β promoter was mediated by a short specific region of the promoter which contains a binding site for STAT-3. Cytokines and Hsps, were quantified in individual blood samples from patients with SLE. Levels of Hsp 90 positively correlated with levels of IL-6 but not IL-10, in patients with SLE. Furthermore, this correlation was enhanced in patients who overexpressed Hsp 90 (a subset of patients associated with HLA DR3 negativity). A link between Hsp 90 overexpression and the development of Hsp 90 autoantibodies was also investigated. Antibodies to Hsps in patients with SLE were quantified. Overexpression of Hsp 90 in SLE correlated with raised levels of antibodies to Hsp 90 in the same patients. Furthermore, antibodies to Hsp 90 were associated with active general disease features of SLE. These results support a role for IL-6 in the overexpression of Hsp 90, leading to raised levels of antibodies to Hsp 90 and active disease in SLE.

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