摘要：SummaryHistone deacetylases (HDACs) are critical immune regulators. However, their roles in interleukin-1β (IL-1β) production remain unclear. By screening 11 zinc-dependent HDACs with chemical inhibitors, we found that HDAC1 inhibitor, 4-(dimethylamino)-N-[6-(hydroxyamino)-6-oxohexyl]-benzamide (DHOB), enhanced IL-1β production by macrophage and dendritic cells upon TLR4 stimulation orMycobacterium tuberculosisinfection through IL-1β maturation via elevated NLRP3 expression, increased cleaved caspase-1, and enhanced ASC oligomerization. DHOB rescued defective IL-1β production by dendritic cells infected withM. tuberculosiswith ESAT-6 deletion, a virulence factor shown to activate NLRP3 inflammasome. DHOB increased IL-1β production and NLRP3 expression in a tuberculosis mouse model. Although DHOB inhibited HDAC activities of both HDAC1 and HDAC2 by direct binding, knockdown of HDAC2, but not HDAC1, increased IL-1β production and NLRP3 expression inM. tuberculosis-infected macrophages. These data suggest that HDAC2, but not HDAC1, controls IL-1β production through NLRP3 inflammasome activation, a mechanism with a significance in chronic inflammatory diseases including tuberculosis.Graphical abstractDisplay OmittedHighlights•HDAC1 inhibitor, DHOB, increased IL-1β production via NLRP3 inflammasome activation•DHOB suppressed deacetylase activities of both HDAC1 and HDAC2 by direct interaction•Deletion of HDAC2, but not HDAC1, increased IL-β production by increased NLRP3 expression•DHOB increased IL-1β and NLRP3 expression in a mouse model of TB infectionBiochemistry; Immunology; Microbiology
