Abstract
We previously demonstrated that the organic extract of Spirulina platensis (SPE), an edible blue-green alga, possesses potent anti-inflammatory effects. In this study, we investigated if the regulation of histone deacetylases (HDACs) play a role in the anti-inflammatory effect of SPE in macrophages. Treatment of macrophages with SPE rapidly and dose-dependently reduced HDAC2, 3, and 4 proteins which preceded decreases in their mRNA levels. Degradation of HDAC4 protein was attenuated in the presence of inhibitors of calpain proteases, lysosomal acidification, and Ca2+/calmodulin-dependent protein kinase II, respectively, but not a proteasome inhibitor. Acetylated histone H3 was increased in SPE-treated macrophages to a similar level as macrophages treated with a pan-HDAC inhibitor, with concomitant inhibition of inflammatory gene expression upon LPS stimulation. Knockdown of HDAC3 increased basal and LPS-induced pro-inflammatory gene expression, while HDAC4 knockdown increased basal expression of interleukin-1β (IL-1β), but attenuated LPS-induced inflammatory gene expression. Chromatin immunoprecipitation showed that SPE decreased p65 binding and H3K9/K14 acetylation at the Il-1β and tumor necrosis factor α (Tnfα) promoters. Our results suggest that SPE increased global histone H3 acetylation by facilitating HDAC protein degradation, but decreases histone H3K9/K14 acetylation and p65 binding at the promoters of Il-1β and Tnfα to exert its anti-inflammatory effect.
Highlights
Chronic inflammation is causally linked to the pathogenesis of obesity-induced metabolic diseases, such as insulin resistance, type 2 diabetes, cardiovascular disease (CVD) and non-alcoholic fatty liver disease [1,2]
We found that knockdown of HDAC4 increased the basal expression of IL-1β, suggesting that it participate in the active repression of IL-1β, but not IL-6 and tumor necrosis factor α (TNFα)
Our present study demonstrated that Spirulina platensis (SPE) facilitates the protein degradation of several histone deacetylases (HDACs) isoforms and inhibits their mRNA transcription, increasing global acetylated histone H3 in macrophages
Summary
Chronic inflammation is causally linked to the pathogenesis of obesity-induced metabolic diseases, such as insulin resistance, type 2 diabetes, cardiovascular disease (CVD) and non-alcoholic fatty liver disease [1,2]. Pro-inflammatory cytokines, including tumor necrosis factor α (TNFα), interleukin-6. (IL-6) and interleukin-1β (IL-1β), have shown to deteriorate normal cellular functions, leading to the metabolic diseases [3,4]. Recent studies utilizing inhibitors and genetic ablation of histone deacetylases (HDACs) have suggested that HDACs are obligatory for optimal induction of inflammatory gene expression in macrophages [5,6,7,8]. HDAC inhibitors have emerged as anti-inflammatory agents. HDACs are epigenetic regulators of gene transcription by catalyzing the removal of acetyl moieties from lysine residues on histone tails, which is generally associated with transcriptional repression [9]. HDACs are classified based on their phylogeny. Class I HDACs, i.e., HDAC1, 2, 3 and
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