Histone deacetylase inhibitors induce apoptosis in human eosinophils and neutrophils

Journal of Inflammation

Research

Kazuhiro Ito¹  Ian M Adcock¹  Misako Ito¹  Pinja Ilmarinen-Salo²  Mirkka Janka-Junttila²  Eeva Moilanen²  Xianzhi Zhang²  Ulla Jalonen²  Hannu Kankaanranta³ 

[1] Airway Disease, Imperial College School of Medicine at the National Heart and Lung Institute, London, UK;The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, FIN-33014, Tampere, Finland;The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, FIN-33014, Tampere, Finland;Department of Respiratory Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland;

关键词: Chronic Obstructive Pulmonary Disease;    Glucocorticoid;    Budesonide;    Nuclear Extract;    Fluticasone;   

DOI  :  10.1186/1476-9255-7-9

 received in 2009-04-08, accepted in 2010-02-04,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundGranulocytes are important in the pathogenesis of several inflammatory diseases. Apoptosis is pivotal in the resolution of inflammation. Apoptosis in malignant cells is induced by histone deacetylase (HDAC) inhibitors, whereas HDAC inhibitors do not usually induce apoptosis in non-malignant cells. The aim of the present study was to explore the effects of HDAC inhibitors on apoptosis in human eosinophils and neutrophils.MethodsApoptosis was assessed by relative DNA fragmentation assay, annexin-V binding, and morphologic analysis. HDAC activity in nuclear extracts was measured with a nonisotopic assay. HDAC expression was measured by real-time PCR.ResultsA HDAC inhibitor Trichostatin A (TSA) induced apoptosis in the presence of survival-prolonging cytokines interleukin-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) in eosinophils and neutrophils. TSA enhanced constitutive eosinophil and neutrophil apoptosis. Similar effects were seen with a structurally dissimilar HDAC inhibitor apicidin. TSA showed additive effect on the glucocorticoid-induced eosinophil apoptosis, but antagonized glucocorticoid-induced neutrophil survival. Eosinophils and neutrophils expressed all HDACs at the mRNA level except that HDAC5 and HDAC11 mRNA expression was very low in both cell types, HDAC8 mRNA was very low in neutrophils and HDAC9 mRNA low in eosinophils. TSA reduced eosinophil and neutrophil nuclear HDAC activities by ~50-60%, suggesting a non-histone target. However, TSA did not increase the acetylation of a non-histone target NF-κB p65. c-jun-N-terminal kinase and caspases 3 and 6 may be involved in the mechanism of TSA-induced apoptosis, whereas PI3-kinase and caspase 8 are not.ConclusionsHDAC inhibitors enhance apoptosis in human eosinophils and neutrophils in the absence and presence of survival-prolonging cytokines and glucocorticoids.

【 授权许可】

CC BY   
© Kankaanranta et al; licensee BioMed Central Ltd. 2010