title: Histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits anti-inflammatory activities through induction of mitochondrial damage and apoptosis in activated lymphocytes.
abstract: Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, has been proven to be an anti-cancer agent. Its anti-inflammatory activities have recently been observed both in in vitro and in vivo models. Yet its action on lymphocytes and the underlying mechanism are still not well known. In this study, in order to evaluate the anti-inflammatory function of SAHA, we analyzed the effects of SAHA on the proliferation, activation, cytokines secretion, cell cycle distribution and apoptosis of murine lymphocytes activated with concanavalin A (Con A). Our results demonstrated that SAHA inhibited the proliferation of Con A-activated lymphocytes in a dose-dependent manner. The expression of CD69 on CD3(+) T lymphocytes was significantly inhibited by SAHA. Intracellular cytokine staining analysis showed that SAHA could downregulate the expression of pro-inflammatory cytokines TNF-α, IL-6 and IFN-γ in T lymphocytes. Furthermore, analysis of sub-G(0)/G(1) peaks and annexin V binding populations revealed that SAHA induced apoptotic cell death in Con A-activated lymphocytes. Consistent with these results, SAHA treatment also induced a decrease of mitochondrial membrane potential and cleavage of caspase-3 and PARP in these cells. Moreover, SAHA caused an accumulation of phosphorylated histone H2A.X, indicating increased double strand DNA breaks. These findings suggest that induction of apoptosis through the mitochondrial pathway may contribute to the anti-inflammatory activities of SAHA on activated lymphocytes.
authors.affiliation: Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou 510632, PR China.
authors.forename: Zi-jian
authors.initials: ZJ
authors.lastname: Shi
authors.forename: Dong-yun
authors.initials: DY
authors.lastname: Ouyang
authors.forename: Jun-shan
authors.initials: JS
authors.lastname: Zhu
authors.forename: Li-hui
authors.initials: LH
authors.lastname: Xu
authors.forename: Xian-hui
authors.initials: XH
authors.lastname: He
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D037181:Lectins, C-Type / Q000276:immunology; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D000077337:Vorinostat; D000099192:CD69 Antigens
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D003208:Concanavalin A; D016207:Cytokines; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D037181:Lectins, C-Type; D000077337:Vorinostat; D000099192:CD69 Antigens