Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse
Nilamadhab Mishra, … , Phil Ruiz, Gary S. Gilkeson
Nilamadhab Mishra, … , Phil Ruiz, Gary S. Gilkeson
Published February 15, 2003
Citation Information: J Clin Invest. 2003;111(4):539-552. https://doi.org/10.1172/JCI16153.
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Article Autoimmunity

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

Abstract

Studies in human systemic lupus erythematosus (SLE) suggest a possible role for histone deacetylases (HDACs) in skewed gene expression and disease pathogenesis. We used the MRL-lpr/lpr murine model of lupus to demonstrate that HDACs play a key role in the heightened levels of both Th1 and Th2 cytokine expression that contribute to disease. The availability of specific HDAC inhibitors (HDIs) such as trichostatin A (TSA) and suberonylanilide hydroxamic acid (SAHA) permits the study of the role of HDACs in gene regulation. Our results indicate that HDIs downregulate IL-12, IFN-γ, IL-6, and IL-10 mRNA and protein levels in MRL-lpr/lpr splenocytes. This effect on gene transcription is associated with an increased accumulation of acetylated histones H3 and H4 in total cellular chromatin. To elucidate the in vivo effects of TSA on lupuslike disease, we treated MRL-lpr/lpr mice with TSA (0.5 mg/kg/d) for 5 weeks. Compared with vehicle-treated control mice, TSA-treated mice exhibited a significant reduction in proteinuria, glomerulonephritis, and spleen weight. Taken together, these findings suggest that increased expression of HDACs leading to an altered state of histone acetylation may be of pathologic significance in MRL-lpr/lpr mice. In addition, TSA or other HDIs may have therapeutic benefit in the treatment of SLE.

Authors

Nilamadhab Mishra, Christopher M. Reilly, Doris R. Brown, Phil Ruiz, Gary S. Gilkeson

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Figure 1

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Downregulation of IFN-γ transcript and protein levels by TSA and SAHA. (...
Downregulation of IFN-γ transcript and protein levels by TSA and SAHA. (a) TSA (300–500 ng/ml) decreases the level of IFN-γ mRNA relative to GAPDH mRNA in splenocytes from 24-week-old MRL-lpr/lpr mice. (b) Splenocytes from 10-week-old MRL-lpr/lpr mice were incubated in the absence or presence of 300 ng/ml TSA or 10 μM SAHA for 18 hours. Splenocytes were then stimulated with ConA (10 μg/ml) for 18 hours. In lanes 3 and 5, TSA or SAHA was added at the same time as ConA and cultured for 18 hours. IFN-γ mRNA levels relative to GAPDH are shown. (c) Based on densitometric scanning of the gel in b, this graph depicts the fold change of IFN-γ mRNA in cells cultured as described above. A representative of three independent experiments is shown. (d) Splenocytes from 10-week-old mice were cultured in the presence of vehicle, LPS, LPS plus TSA, LPS plus SAHA, ConA, ConA plus TSA, or ConA plus SAHA for 72 hours. The concentrations of TSA and SAHA were 300 ng/ml and 10 μM, respectively. This graph depicts the amount of IFN-γ protein secretion. The bar represents the mean ± SEM of three independent experiments.