Interleukin-10 activates heat-shock protein 90beta gene expression.
Elevated levels of the cytokine interleukin-10 (IL-10) have been reported in patients with active systemic lupus erythematosus (SLE). Any role for IL-10 in the pathogenesis of SLE is likely to involve the activation of expression of specific genes within its target cells. We have previously reported elevated levels of the 90 000 MW heat-shock protein (hsp 90) and autoantibodies to hsp 90 in patients with SLE. Recent studies have shown that the cytokine IL-6 activates hsp 90 gene expression via specific transcription factors that include STAT-3 (signal transducer and activator of transcription 3). In view of the known role of STAT proteins in IL-10 signalling pathways, we have investigated the effect of IL-10 on hsp 90 gene expression. Here we report that IL-10 enhances the expression of hsp 90 in both a human hepatoma cell line (HepG2) stably expressing the human IL-10 receptor and peripheral blood mononuclear cells (PBMC). In reporter gene assays IL-10 is able to activate both the hsp 90alpha and hsp 90beta promoters directly. Furthermore, a short region of the hsp 90beta promoter which is activated in response to IL-10, contains a STAT-3 binding site. This element but not a mutant derivative unable to bind STAT-3, is able to confer a response to IL-10 on a heterologous promoter. These results may be understood in terms of the shared signalling mechanisms of IL-10 and IL-6 and provide evidence of a role for IL-10 in the overexpression of hsp 90 in SLE, with possible pathological consequences.
Ripley
B J
BJ
Department of Molecular Pathology, The Windeyer Institute of Medical Sciences, University College London, London, UK.
Stephanou
A
A
Isenberg
D A
DA
Latchman
D S
DS
D000209:Acute-Phase Proteins / Q000378:metabolism; D018929:Cell Culture Techniques; D004268:DNA-Binding Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000209:Acute-Phase Proteins; D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D016753:Interleukin-10