Stammler, Dominik and Eigenbrod, Tatjana and Menz, Sarah and Frick, Julia S. and Sweet, Matthew J. and Shakespear, Melanie R. and Jantsch, Jonathan and Siegert, Isabel and Woelfle, Sabine and Langer, Julian D. and Oehme, Ina and Schaefer, Liliana and Fischer, Andre and Knievel, Judith and Heeg, Klaus and Dalpke, Alexander H. and Bode, Konrad A. (2015) Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1 beta via a Caspase-1-Independent Mechanism. JOURNAL OF IMMUNOLOGY, 195 (11). pp. 5421-5431. ISSN 0022-1767, 1550-6606
Full text not available from this repository. (Request a copy)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-1 beta processing and secretion in human and murine dendritic cells and murine macrophages. HDACi/LPS-induced IL-1 beta maturation and secretion kinetics differed completely from those observed upon inflammasome activation. Moreover, this pathway of IL-1 beta 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-1 beta, confirming that this pathway is also operative in vivo. Thus, in addition to the conventional inflammasome-dependent IL-1 beta cleavage pathway, dendritic cells and macrophages are capable of generating, secreting, and processing bioactive IL-1 beta by a novel, caspase-8-dependent mechanism. Given the widespread interest in the therapeutic targeting of IL-1 beta, as well as the use of HDACi for anti-inflammatory applications, these findings have substantial clinical implications.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHAIN FATTY-ACIDS; HDAC INHIBITORS; MICE DEFICIENT; INFLAMMATORY RESPONSES; INNATE IMMUNITY; GRANZYME-A; INTERLEUKIN-1-BETA; ACTIVATION; RECEPTOR; ARTHRITIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 May 2019 08:11 |
| Last Modified: | 07 May 2019 08:11 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4405 |
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