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

Cell Mol Immunol. 2012 May;9(3):255-66. doi: 10.1038/cmi.2012.5. Epub 2012 Apr 30.


Elevated expression of heat shock protein 90 (HSP90) has been found in kidneys and serum of systemic lupus erythematosus (SLE) patients and MRL/Mp-Fas(lpr)/Fas(lpr) (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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Antinuclear / immunology
  • Benzoquinones / administration & dosage
  • Benzoquinones / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Disease Models, Animal
  • HSP90 Heat-Shock Proteins* / antagonists & inhibitors
  • Humans
  • Interleukin-12 / metabolism
  • Interleukin-6 / metabolism
  • Lactams, Macrocyclic / administration & dosage
  • Lactams, Macrocyclic / pharmacology
  • Lupus Erythematosus, Systemic / drug therapy
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation / drug effects
  • Mesangial Cells / drug effects
  • Mesangial Cells / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Nitric Oxide / metabolism


  • Antibodies, Antinuclear
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Interleukin-6
  • Lactams, Macrocyclic
  • 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
  • Interleukin-12
  • Nitric Oxide