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The Histone Deacetylase Inhibitor Trichostatin A is a Potent Inhibitor of Cytokine Release from Mouse Peripheral Blood Mononuclear Cells and Human Monocytes
Author(s) -
Linnevers Christopher John,
Chen Albert,
McCluskie Kerryn,
Yu Cecile,
Wilson Richard,
Yang Alfred,
Klein Uwe
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a442-c
Subject(s) - trichostatin a , peripheral blood mononuclear cell , histone deacetylase inhibitor , chemistry , histone deacetylase , lipopolysaccharide , cytokine , microbiology and biotechnology , tumor necrosis factor alpha , interleukin , pharmacology , immunology , in vitro , biochemistry , biology , histone , gene
Reversible acetylation of nuclear histones plays a critical role in the regulation of pro‐inflammatory gene transcription. Here we describe the effects of the non‐selective histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), on the release of pro‐inflammatory cytokines from stimulated mouse peripheral blood mononuclear cells (PBMC) and human peripheral blood monocytes (PBM). PBMC from BALB/c mice and PBM from healthy human donors were treated with TSA and stimulated with lipopolysaccharide (LPS) or interleukin (IL)‐1β for 24 hours. Cytokines released into the culture medium were quantified by immunoassay, and total HDAC activity was determined by fluorogenic assay. TSA (33nM) inhibited >80% of LPS‐stimulated TNFα and >60% of MIP‐2 release from PBMC isolated from both naïve and ovalbumin‐sensitized mice. TSA was similarly effective at inhibiting LPS and IL‐1β‐stimulated release of TNFα, GM‐CSF, and to a lesser extent, IL‐8 from human PBM. In live PBMC, TSA and suberoylanilide hydroxamic acid (SAHA) inhibited total HDAC activity with pIC50 values of 7.8 (±0.3) and 6.2 (±0.1), respectively, which correlated well with pIC50 values for inhibition of TNFα release of 7.9 (±0.1) and 6.1 (±0.3), respectively. Future studies will address which HDAC isotypes are involved in the regulation of cytokine expression and release. Abstract funded by Theravance, Inc.