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Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus

Cellular & Molecular Immunology volume 9, pages 255–266 (2012)Cite this article

Abstract

Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Faslpr/Faslpr (MRL/lpr) autoimmune mice. We investigated if inhibition of HSP90 would reduce disease in MRL/lpr mice. In vitro, pretreatment of mesangial cells with HSP90 inhibitor Geldanamycin prior to immune-stimulation showed reduced expression of IL-6, IL-12 and NO. In vivo, we found HSP90 expression was elevated in MRL/lpr kidneys when compared to C57BL/6 mice and MRL/lpr mice treated with HSP90 inhibitor 17-DMAG. MRL/lpr mice treated with 17-DMAG showed decreased proteinuria and reduced serum anti-dsDNA antibody production. Glomerulonephritis and glomerular IgG and C3 were not significantly affected by administration of 17-DMAG in MRL/lpr. 17-DMAG increased CD8+ T cells, reduced double-negative T cells, decreased the CD4/CD8 ratio and reduced follicular B cells. These studies suggest that HSP90 may play a role in regulating T-cell differentiation and activation and that HSP90 inhibition may reduce inflammation in lupus.

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Acknowledgements

We would like to acknowledge the assistance that Melissa Makris provided with the flow cytometry. We would also like to thank the animal care staff at VMRCVM for their attention to our animals. We are appreciative of the support by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

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Authors and Affiliations

  1. Virginia Tech-Wake Forest School of Biomedical Engineering and Science, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA

    Samuel K Shimp III, Molly A Read & MarissaNichole Rylander

  2. Department of Biomedical Sciences and Pathobiology, Virginia–Maryland Regional College of Veterinary Medicine, Blacksburg, VA, USA

    Cristen B Chafin, Nicole L Regna, Sarah E Hammond, David L Caudell & Christopher M Reilly

  3. Edward Via College of Osteopathic Medicine, Blacksburg, VA, USA

    Christopher M Reilly

  4. Department of Mechanical Engineering, Virginia Polytechinc Institue and State University, Blacksburg, VA, USA

    MarissaNichole Rylander

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  1. Samuel K Shimp III
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  8. Christopher M Reilly
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Correspondence to Samuel K Shimp III.

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Shimp, S., Chafin, C., Regna, N. et al. Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus. Cell Mol Immunol 9, 255–266 (2012). https://doi.org/10.1038/cmi.2012.5

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  • DOI: https://doi.org/10.1038/cmi.2012.5

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