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Interleukin-10 activates heat-shock protein 90beta gene expression
B J Ripley1, A Stephanou, D A Isenberg
1Department of Molecular Pathology, The Windeyer Institute of Medical Sciences, University College London, London, UK.
Immunology
|August 14, 1999
Summary
Interleukin-10 (IL-10) increases heat-shock protein 90 (hsp 90) expression in cells, potentially explaining hsp 90 overexpression in systemic lupus erythematosus (SLE) and its pathological effects.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Biology
Background:
- Elevated interleukin-10 (IL-10) levels are observed in active systemic lupus erythematosus (SLE).
- Heat-shock protein 90 (hsp 90) and autoantibodies to hsp 90 are also elevated in SLE patients.
- Interleukin-6 (IL-6) activates hsp 90 gene expression via STAT-3, and STAT proteins are involved in IL-10 signaling.
Purpose of the Study:
- To investigate the effect of IL-10 on hsp 90 gene expression.
- To determine if IL-10 directly activates hsp 90 gene expression.
- To elucidate the signaling pathway involved in IL-10-mediated hsp 90 expression.
Main Methods:
- Reporter gene assays were used to assess hsp 90 promoter activity.
- Experiments were conducted in a human hepatoma cell line (HepG2) and peripheral blood mononuclear cells (PBMC).
- Site-directed mutagenesis was employed to examine the role of a STAT-3 binding site in the hsp 90beta promoter.
Main Results:
- IL-10 enhances hsp 90 expression in both HepG2 cells and PBMC.
- IL-10 directly activates the promoters of hsp 90alpha and hsp 90beta.
- A STAT-3 binding site within the hsp 90beta promoter mediates the IL-10 response.
Conclusions:
- IL-10 directly upregulates hsp 90 gene expression through a STAT-3 dependent mechanism.
- Shared signaling pathways between IL-10 and IL-6 may explain hsp 90 overexpression in SLE.
- IL-10 may contribute to the pathology of SLE via the overexpression of hsp 90.