Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse

Abstract

Nonstandard abbreviations used: systemic lupus erythematosus (SLE); double-stranded DNA (dsDNA); glomerulonephritis (GN); recombinant IL-12 (rIL-12); recombinant IFN-γ (rIFN-γ); concanavalin A (ConA); histone deacetylase (HDAC); histone deacetylase inhibitor (HDI); trichostatin A (TSA); suberonylanilide hydroxamic acid (SAHA); body weight (BW); PBS containing 0.05% Tween (PBS-T); glomerular basement membrane (GBM).including anti-double-stranded DNA (anti-dsDNA) autoantibodies and hypocomplementemia by 12-16 weeks of age; and (c) clinical signs of arthritis, massive lymphadenopathy, splenomegaly, vasculitis, and glomerulonephritis (GN) by the age of 16-24 weeks.Fifty percent of MRL-lpr/lpr mice die by 24 weeks of age, primarily from renal failure (2).Although the etiology of SLE is unknown, a number of key mediators of disease have been identified.Cytokines produced by Th1 and Th2 lymphocytes play a major role in the immunopathogenesis of human and murine SLE (3).Studies of cytokine mRNA and protein in MRLlpr/lpr mice with established disease have documented that splenic Th1 and Th2 subsets are constitutively activated (4).These T cells produce heightened levels of specific cytokines that contribute directly to the aberrant immune response that ultimately leads to dysregulated autoantibody production (3, 4).IFN-γ is a Th1 cytokine that enhances production of IgG2a and IgG3; moreover, this cytokine accelerates GN in both NZB/W F 1 and MRL-lpr/lpr murine models of SLE.In vivo administration of IFN-γ accelerates the disease process, whereas treatment with monoclonal anti-IFN-γ antibody or soluble IFN-γ receptor significantly delays the disease in NZB/W F 1 mice and, to a lesser extent, in MRL-lpr/lpr mice (5, 6). IL-12 is also a Th1 cytokine that promotes differentiation of Th1 CD4 + cells. Administration of IL-12 accelerates GN by promoting intrarenal accumulation