title: Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus.
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-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.
authors.affiliation: Virginia Tech-Wake Forest School of Biomedical Engineering and Science, Virginia Polytechnic Institute and State University, Blacksburg, VA 21061, USA. sshimp@vt.edu
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Shimp
authors.forename: Cristen B
authors.initials: CB
authors.lastname: Chafin
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Regna
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hammond
authors.forename: Molly A
authors.initials: MA
authors.lastname: Read
authors.forename: David L
authors.initials: DL
authors.lastname: Caudell
authors.forename: Marissanichole
authors.initials: M
authors.lastname: Rylander
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Reilly
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D050527:Mesangial Cells / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D009569:Nitric Oxide / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D018664:Interleukin-12; D009569:Nitric Oxide