The histone deacetylase inhibitor Trichostatin A modulates CD4+ T cell responses
Open Access
- 9 November 2003
- journal article
- Published by Springer Nature in BMC Cancer
- Vol. 3 (1), 30
- https://doi.org/10.1186/1471-2407-3-30
Abstract
Histone deacetylase inhibitors (HDACIs) induce hyperacetylation of core histones modulating chromatin structure and affecting gene expression. These compounds are also able to induce growth arrest, cell differentiation, and apoptotic cell death of tumor cells in vitro as well as in vivo. Even though several genes modulated by HDAC inhibition have been identified, those genes clearly responsible for the biological effects of these drugs have remained elusive. We investigated the pharmacological effect of the HDACI and potential anti-cancer agent Trichostatin A (TSA) on primary T cells. To ascertain the effect of TSA on resting and activated T cells we used a model system where an enriched cell population consisting of primary T-cells was stimulated in vitro with immobilized anti-CD3/anti-CD28 antibodies whilst exposed to pharmacological concentrations of Trichostatin A. We found that this drug causes a rapid decline in cytokine expression, accumulation of cells in the G1 phase of the cell cycle, and induces apoptotic cell death. The mitochondrial respiratory chain (MRC) plays a critical role in the apoptotic response to TSA, as dissipation of mitochondrial membrane potential and reactive oxygen species (ROS) scavengers block TSA-induced T-cell death. Treatment of T cells with TSA results in the altered expression of a subset of genes involved in T cell responses, as assessed by microarray gene expression profiling. We also observed up- as well as down-regulation of various costimulatory/adhesion molecules, such as CD28 and CD154, important for T-cell function. Taken together, our findings indicate that HDAC inhibitors have an immunomodulatory potential that may contribute to the potency and specificity of these antineoplastic compounds and might be useful in the treatment of autoimmune disorders.Keywords
This publication has 75 references indexed in Scilit:
- Post-activation Turn-off of NF-κB-dependent Transcription Is Regulated by Acetylation of p65Journal of Biological Chemistry, 2003
- How cells die: Apoptosis pathwaysJournal of Allergy and Clinical Immunology, 2001
- Histone Hyperacetylation Induced by Histone Deacetylase Inhibitors Is Not Sufficient to Cause Growth Inhibition in Human Dermal FibroblastsJournal of Biological Chemistry, 2001
- Inhibition of Mitogenesis in Balb/c-3T3 Cells by Trichostatin APublished by Elsevier ,2000
- Butyrate inhibits inflammatory responses through NFkappa B inhibition: implications for Crohn's diseaseGut, 2000
- Phosphorylation Meets Ubiquitination: The Control of NF-κB ActivityAnnual Review of Immunology, 2000
- CTLA-4 Ligation Suppresses CD28-induced NF-κB and AP-1 Activity in Mouse T Cell BlastsJournal of Biological Chemistry, 1999
- NF-κB AND REL PROTEINS: Evolutionarily Conserved Mediators of Immune ResponsesAnnual Review of Immunology, 1998
- Distinct interactions of PML-RARα and PLZF-RARα with co-repressors determine differential responses to RA in APLNature Genetics, 1998
- THE NF-κB AND IκB PROTEINS: New Discoveries and InsightsAnnual Review of Immunology, 1996