MilliporeSigma
  • Home
  • Search Results
  • Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1β via a Caspase-1-Independent Mechanism.

Inhibition of Histone Deacetylases Permits Lipopolysaccharide-Mediated Secretion of Bioactive IL-1β via a Caspase-1-Independent Mechanism.

Journal of immunology (Baltimore, Md. : 1950) (2015-11-01)
Dominik Stammler, Tatjana Eigenbrod, Sarah Menz, Julia S Frick, Matthew J Sweet, Melanie R Shakespear, Jonathan Jantsch, Isabel Siegert, Sabine Wölfle, Julian D Langer, Ina Oehme, Liliana Schaefer, Andre Fischer, Judith Knievel, Klaus Heeg, Alexander H Dalpke, Konrad A Bode
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Resiquimod, ≥98% (HPLC)
Sigma-Aldrich
MS-275, A HDAC1 and HDAC3 inhibitor
Sigma-Aldrich
Pimelic Diphenylamide 106, ≥98% (HPLC)
Sigma-Aldrich
MC1568, ≥97% (HPLC)
Sigma-Aldrich
Imiquimod, ≥98% (HPLC), solid
Sigma-Aldrich
M344, ≥98% (HPLC), powder
Sigma-Aldrich
Sodium deoxycholate, BioXtra, ≥98.0% (dry matter, NT)
Sigma-Aldrich
Z-Ile-Glu(O-ME)-Thr-Asp(O-Me) fluoromethyl ketone, ≥90% (TLC), powder
Sigma-Aldrich
Sodium butyrate, ≥98.5% (GC)
Sigma-Aldrich
Sodium deoxycholate, ≥97% (titration)
Sigma-Aldrich
Trichostatin A, ≥98% (HPLC), from Streptomyces sp.
SAFC
Sodium deoxycholate
Sigma-Aldrich
SAHA, ≥98% (HPLC)
SAFC
Sodium butyrate
Sigma-Aldrich
Sodium butyrate, 98%