title: Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1β via a Caspase-1-Independent Mechanism.
abstract: Histone deacetylase (HDAC) inhibitors (HDACi) are clinically approved anticancer drugs that have important immune-modulatory properties. We report the surprising finding that HDACi promote LPS-induced IL-1β processing and secretion in human and murine dendritic cells and murine macrophages. HDACi/LPS-induced IL-1β maturation and secretion kinetics differed completely from those observed upon inflammasome activation. Moreover, this pathway of IL-1β secretion was dependent on caspase-8 but was independent of the inflammasome components NACHT, LRR, and PYD domains-containing protein 3, apoptosis-associated speck-like protein containing a carboxyl-terminal caspase-recruitment domain, and caspase-1. Genetic studies excluded HDAC6 and HDAC10 as relevant HDAC targets in this pathway, whereas pharmacological inhibitor studies implicated the involvement of HDAC11. Treatment of mice with HDACi in a dextran sodium sulfate-induced colitis model resulted in a strong increase in intestinal IL-1β, confirming that this pathway is also operative in vivo. Thus, in addition to the conventional inflammasome-dependent IL-1β cleavage pathway, dendritic cells and macrophages are capable of generating, secreting, and processing bioactive IL-1β by a novel, caspase-8-dependent mechanism. Given the widespread interest in the therapeutic targeting of IL-1β, as well as the use of HDACi for anti-inflammatory applications, these findings have substantial clinical implications.
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg 69120, Germany;
authors.forename: Dominik
authors.initials: D
authors.lastname: Stammler
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg 69120, Germany;
authors.forename: Tatjana
authors.initials: T
authors.lastname: Eigenbrod
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen 70276, Germany;
authors.forename: Sarah
authors.initials: S
authors.lastname: Menz
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen 70276, Germany;
authors.forename: Julia S
authors.initials: JS
authors.lastname: Frick
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, St. Lucia, Queensland 4072, Australia;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, St. Lucia, Queensland 4072, Australia;
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Shakespear
authors.affiliation: Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg 93053, Germany; Institute of Microbiology, University of Erlangen-Nuremberg, Erlangen 91054, Germany;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jantsch
authors.affiliation: Institute of Microbiology, University of Erlangen-Nuremberg, Erlangen 91054, Germany;
authors.forename: Isabel
authors.initials: I
authors.lastname: Siegert
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg 69120, Germany;
authors.forename: Sabine
authors.initials: S
authors.lastname: Wölfle
authors.affiliation: Department of Molecular Membrane Biology, Max-Planck-Institute for Biophysics, Frankfurt 60438, Germany;
authors.forename: Julian D
authors.initials: JD
authors.lastname: Langer
authors.affiliation: Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center, Heidelberg 69120, Germany;
authors.forename: Ina
authors.initials: I
authors.lastname: Oehme
authors.affiliation: Institute of Pharmacology, Goethe University Frankfurt, Frankfurt 60590, Germany;
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.affiliation: German Center for Neurodegenerative Diseases, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen 37077, Germany; and.
authors.forename: Andre
authors.initials: A
authors.lastname: Fischer
authors.affiliation: Department of Gastroenterology, Hepatology, and Infectious Disease, University Hospital, Heinrich Heine University of Düsseldorf, Düsseldorf 40225, Germany.
authors.forename: Judith
authors.identifier: http://orcid.org/0000-0003-0974-7402
authors.initials: J
authors.lastname: Knievel
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg 69120, Germany;
authors.forename: Klaus
authors.initials: K
authors.lastname: Heeg
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg 69120, Germany;
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Dalpke
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, Heidelberg University Hospital, Heidelberg 69120, Germany; konrad.bode@uni-heidelberg.de.
authors.forename: Konrad A
authors.identifier: http://orcid.org/0000-0001-9085-965X
authors.initials: KA
authors.lastname: Bode
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002352:Carrier Proteins; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology; D053181:Caspase 8 / Q000276:immunology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000235:genetics; D053471:Caspases, Initiator; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced; D003713:Dendritic Cells / Q000276:immunology*; D016264:Dextran Sulfate; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D061945:Caspase Inhibitors; D056572:Histone Deacetylase Inhibitors; C587672:IL1B protein, mouse; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016264:Dextran Sulfate; C101136:Casp4 protein, mouse; D053181:Caspase 8; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1; C528111:Hdac11 protein, mouse; D006655:Histone Deacetylases