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PMID: 12588892 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The Journal of clinical investigation ·Vol. 111 ·No. 4 ·2003-02-00 ·Pages 539-52

Mishra N, Reilly CM, Brown DR, Ruiz P, Gilkeson GS

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-gamma, 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.

MeSH Terms
Animals Autoantibodies/blood Down-Regulation/drug effects Enzyme Inhibitors/pharmacology Female Histone Deacetylase Inhibitors Humans Hydroxamic Acids/pharmacology Interferon-gamma/genetics,metabolism Interleukin-10/genetics,metabolism Interleukin-12/genetics,metabolism Interleukin-6/genetics,metabolism Kidney/drug effects,enzymology,immunology Lupus Erythematosus, Systemic/drug therapy,enzymology,genetics,immunology Mice Mice, Inbred MRL lpr RNA, Messenger/genetics,metabolism Vorinostat
Chemicals
Autoantibodies Enzyme Inhibitors Histone Deacetylase Inhibitors Hydroxamic Acids Interleukin-6 RNA, Messenger Interleukin-10 Interleukin-12 trichostatin A Vorinostat Interferon-gamma
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Mishra Nilamadhab
Section on Rheumatology and Clinical Immunology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. nmishra@wfubmc.edu
Reilly Christopher M
Brown Doris R
Ruiz Phil
Gilkeson Gary S
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI16153
Email
nmishra@wfubmc.edu
Published
2003-02-00
Pages
539-52
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC151922
Subset
IM
Grants
NIAID NIH HHS · F32 AI010582 · United States
NIAMS NIH HHS · R21 AR049153 · United States
NIAMS NIH HHS · AR 49153 · United States
NIAID NIH HHS · F32 AI10582 · United States
External Links
PubMed source DOI: 10.1172/JCI16153 PMC Full Text View journal details
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