Abstract:
:Regulated by histone acetyltransferases and deacetylases (HDACs), histone acetylation is a key epigenetic mechanism controlling chromatin structure, DNA accessibility, and gene expression. HDAC inhibitors induce growth arrest, differentiation, and apoptosis of tumor cells and are used as anticancer agents. Here we describe the effects of HDAC inhibitors on microbial sensing by macrophages and dendritic cells in vitro and host defenses against infection in vivo. HDAC inhibitors down-regulated the expression of numerous host defense genes, including pattern recognition receptors, kinases, transcription regulators, cytokines, chemokines, growth factors, and costimulatory molecules as assessed by genome-wide microarray analyses or innate immune responses of macrophages and dendritic cells stimulated with Toll-like receptor agonists. HDAC inhibitors induced the expression of Mi-2β and enhanced the DNA-binding activity of the Mi-2/NuRD complex that acts as a transcriptional repressor of macrophage cytokine production. In vivo, HDAC inhibitors increased the susceptibility to bacterial and fungal infections but conferred protection against toxic and septic shock. Thus, these data identify an essential role for HDAC inhibitors in the regulation of the expression of innate immune genes and host defenses against microbial pathogens.
journal_name
Bloodjournal_title
Bloodauthors
Roger T,Lugrin J,Le Roy D,Goy G,Mombelli M,Koessler T,Ding XC,Chanson AL,Reymond MK,Miconnet I,Schrenzel J,François P,Calandra Tdoi
10.1182/blood-2010-05-284711subject
Has Abstractpub_date
2011-01-27 00:00:00pages
1205-17issue
4eissn
0006-4971issn
1528-0020pii
blood-2010-05-284711journal_volume
117pub_type
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