Inhibition of histone deacetylases permits lipopolysaccharide-mediated secretion of bioactive IL-1b via a caspase-1-independent mechanism

Stammler, Dominik, Eigenbrod, Tatjana, Menz, Sarah, Frick, Julia S., Sweet, Matthew J., Shakespear, Melanie R., Jantsch, Jonathan, Siegert, Isabel, Wolfle, Sabine, Langer, Julian D., Oehme, Ina, Schaefer, Liliana, Fischer, Andre, Knievel, Judith, Heeg, Klaus, Dalpke, Alexander H. and Bode, Konrad A. (2015) Inhibition of histone deacetylases permits lipopolysaccharide-mediated secretion of bioactive IL-1b via a caspase-1-independent mechanism. Journal of Immunology, 195 11: 5421-5431. doi:10.4049/jimmunol.1501195


Author Stammler, Dominik
Eigenbrod, Tatjana
Menz, Sarah
Frick, Julia S.
Sweet, Matthew J.
Shakespear, Melanie R.
Jantsch, Jonathan
Siegert, Isabel
Wolfle, Sabine
Langer, Julian D.
Oehme, Ina
Schaefer, Liliana
Fischer, Andre
Knievel, Judith
Heeg, Klaus
Dalpke, Alexander H.
Bode, Konrad A.
Title Inhibition of histone deacetylases permits lipopolysaccharide-mediated secretion of bioactive IL-1b via a caspase-1-independent mechanism
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
1550-6606
Publication date 2015-10-30
Sub-type Article (original research)
DOI 10.4049/jimmunol.1501195
Open Access Status Not Open Access
Volume 195
Issue 11
Start page 5421
End page 5431
Total pages 11
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Collection year 2016
Language eng
Formatted abstract
Histone deacetylase (HDAC) inhibitors (HDACi) are clinically approved anticancer drugs that have important immunemodulatory properties. We report the surprising finding that HDACi promote LPS-induced IL-1b processing and secretion in human and murine dendritic cells and murine macrophages. HDACi/LPS-induced IL-1b maturation and secretion kinetics differed completely from those observed upon inflammasome activation. Moreover, this pathway of IL-1b 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-1b, confirming that this pathway is also operative in vivo. Thus, in addition to the conventional inflammasome-dependent IL-1b cleavage pathway, dendritic cells and macrophages are capable of generating, secreting, and processing bioactive IL-1b by a novel, caspase-8–dependent mechanism. Given the widespread interest in the therapeutic targeting of IL-1b, as well as the use of HDACi for anti-inflammatory applications, these findings have substantial clinical implications.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Mon, 09 Nov 2015, 13:41:58 EST by Melanie Shakespear on behalf of Institute for Molecular Bioscience