title: Inhibition of Interleukin 1β (IL-1β) Expression by Anthrax Lethal Toxin (LeTx) Is Reversed by Histone Deacetylase 8 (HDAC8) Inhibition in Murine Macrophages.
abstract: Many pathogenic microbes often release toxins that subvert the host's immune responses to render the environment suitable for their survival and proliferation. LeTx is one of the toxins causing immune paralysis by cleaving and inactivating the mitogen-activated protein kinase (MAPK) kinases (MEKs). Here, we show that inhibition of the histone deacetylase 8 (HDAC8) by either the HDAC8-specific inhibitor PCI-34051 or small interference (si)RNAs rendered LeTx-exposed murine macrophages responsive to LPS in pro-IL-1β production. HDAC8 selectively targeted acetylated histone H3 lysine 27 (H3K27Ac), which is known to associate with active enhancers. LeTx induced HDAC8 expression, in part through inhibiting p38 MAPK, which resulted in a decrease of H3K27Ac levels. Inhibition of HDAC8 increased H3K27Ac levels and enhanced NF-κB-mediated pro-IL-1β enhancer and messenger RNA production in LeTx-exposed macrophages. Collectively, this study demonstrates a novel role of HDAC8 in LeTx immunotoxicity and regulation of pro-IL-1β production likely through eRNAs. Targeting HDAC8 could be a strategy for enhancing immune responses in macrophages exposed to LeTx or other toxins that inhibit MAPKs.
authors.affiliation: From the Department of Microbiology and Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario N6G 2V4, Canada.
authors.forename: Soon-Duck
authors.initials: SD
authors.lastname: Ha
authors.affiliation: From the Department of Microbiology and Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario N6G 2V4, Canada.
authors.forename: Chantelle
authors.initials: C
authors.lastname: Reid
authors.affiliation: From the Department of Microbiology and Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario N6G 2V4, Canada.
authors.forename: Shahab
authors.initials: S
authors.lastname: Meshkibaf
authors.affiliation: From the Department of Microbiology and Immunology and Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario N6G 2V4, Canada skim283@uwo.ca.
authors.forename: Sung Ouk
authors.initials: SO
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D006657:Histones; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; C030325:anthrax toxin; D048051:p38 Mitogen-Activated Protein Kinases; C000603105:HDAC8 protein, mouse; D006655:Histone Deacetylases
keywords: anthrax toxin; histone deacetylase (HDAC); interleukin 1 (IL-1); lipopolysaccharide (LPS); transcription enhancer