Ky‐2, a hybrid compound histone deacetylase inhibitor, regulated inflammatory response in LPS‐driven human macrophages

Abstract

Histone deacetylase has attracted much attention as an epigenetic factor, and the modulation of histone and transcription factor acetylation status is important for regulating gene expression. Moreover, histone deacetylase inhibitors are involved in cellular growth and differentiation. In the present study, we examined the effects of Ky‐2, a hybrid‐compound HDAC inhibitor, on inflammatory reactions and the polarization of macrophages in vitro. Human monocyte‐like THP‐1 cells were polarized to macrophage‐like cells using phorbol 12‐myristate 13‐acetate, and then polarized to M1 macrophages with LPS. Ky‐2 inhibited HDAC2 expression and enhanced the acetylation of histone H3 in THP‐1 cells. It also downregulated the expression of the IL‐1β‐encoding gene and the LPS‐induced phosphorylation of p38 mitogen‐activated protein kinases in THP‐1 cells. Moreover, the expression of nod‐like receptor protein 3 and cleaved caspase‐1 p20 was downregulated in Ky‐2‐treated THP‐1 cells. In contrast, this agent upregulated the expression of IL‐1ra in LPS‐treated THP‐1 cells. These results indicate that Ky‐2‐treatment downregulates the expression of the inflammatory cytokine, IL‐1β, in LPS‐treated THP‐1 cells, suggesting that Ky‐2 might regulate M1 macrophage polarization through the suppression of inflammatory responses such as NLRP3 inflammasome activation.

Entinostat Improves Motor Function and Neuronal Damage Via Downregulating NLRP3 Inflammasome Activation After Spinal Cord Injury

“…Previously, correlations between HDAC and NLRP3 have been rarely reported. Ky-2, a hybrid compound HDACi, downregulates LPS-induced NLRP3, caspase-1 p 20, and IL-1β in THP-1 cells that may regulate M1 macrophage polarization via inhibiting NLRP3 inflammasome activation (Kaneko et al, 2018). In J774A.1 cells, hydroxamic acid derivatives of nigranoic acid and manwuweizic acid moderately enhance HDAC1/2/4/6 inhibition activity, which inhibits IL-1β maturation and caspase-1 cleavage, and Ni et al suggest that the synthesis of HDACi may block NLRP3 inflammasome activation (Ni et al, 2021).…”

Role of Epigenetics in the Regulation of Immune Functions of the Skin

“…Other histone acetylases negatively regulate inflammatory cytokine production, including KAT8 (Huai et al, 2019), SIRT2 (Lo Sasso et al, 2014), SIRT3 (Traba et al, 2015), and SIRT6 (Lee et al, 2017). Furthermore, inflammatory responses can differ depending on the method of targeting enzymes responsible for epigenetic modifications (Das Gupta et al, 2020;Fang et al, 2018;Jan et al, 2017;Kaneko et al, 2018;Kitamura et al, 2017;Li et al, 2017b;Lu et al, 2015;Moreno-Gonzalo et al, 2017;Pham et al, 2016;Poralla et al, 2015;Qin et al, 2017;Sanchez et al, 2018;Sano et al, 2018;Sun et al, 2016;Wang et al, 2018Wang et al, , 2017Yang et al, 2014;Zhang et al, 2019b). These findings show that specificity in targeting epigenetic modifications is important to understand therapeutic efficacy.…”

Cytokines and pregnancy: Potential regulation by histone deacetylases

“…Experiments involving many different human cell types have identified HDACs in the regulation of several cytokines and pathways, and it is likely that at least some of these operate in the placenta and gestational membranes (Munro et al, 2013; Shao et al, 2017). In humans, HDAC inhibition selectively alters cytokine messenger RNA (mRNA) expression and protein production by immune cells (Kaneko et al, 2018; Roger et al, 2011). In Th0 cells, HDAC‐1 and HDAC‐2 are recruited to the IFN‐γ locus, and act to repress transcription (Chang et al, 2008).…”

“…Likewise, HDAC‐1 represses transcription of IL‐2 in T‐cells (Lam et al, 2015; J. Wang et al, 2009), and IL‐6 and IL‐12 in macrophages (Lu et al, 2005; Yao et al, 2014) (Figure 3). HDAC inhibition also seems to inhibit proinflammatory cytokine production from activated dendritic cells (Song et al, 2011) and from LPS‐driven human macrophages (Kaneko et al, 2018).…”