Hydrogen sulfide attenuates cytokine production through the modulation of chromatin remodeling

Abstract

Hydrogen sulfide (H2S) is an endogenous gaseous biological mediator, which regulates, among others, the oxidative balance of cells under normal physiological conditions, as well as in various diseases. Several previous studies have reported that H2S attenuates inflammatory mediator production. In this study, we investigated the role of H2S in chromatin modulation in an in vitro model of lipopolysaccharide (LPS)-induced inflammation and evaluated its effects on inflammatory cytokine production. Tamm-Horsfall protein 1 (THP-1) differentiated macrophages were pre-treated with sodium hydrosulfide (NaHS) (an H2S donor) at 0.01, 0.1, 0.5 or 1 mM for 30 min. To stimulate cytokine production, the cells were challenged with bacterial LPS (1 μg/ml) for 1, 4, 8 or 24 h. Histone H3 acetylation was analyzed by chromatin immunoprecipitation (ChIP), cytokine production was measured by ELISA and histone deacetylase (HDAC) activity was analyzed using a standard biochemical assay. H2S inhibited the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in a concentration-dependent manner; it was most effective at the two highest concentrations used. This effect was associated with a decrease in histone H3 acetylation at the IL-6 and TNF-α promoters in the cells exposed to H2S or H2S + LPS. The findings of the present study suggest that H2S suppresses histone acetylation, which, in turn, inhibits chromatin openness, leading to a decrease in the gene transcription of various pro-inflammatory cytokines. Therefore, this mechanism may contribute to the previously demonstrated anti-inflammatory effects of H2S and various H2S donors.

Upregulation of Cystathionine-β-Synthase in Colonic Epithelia Reprograms Metabolism and Promotes Carcinogenesis

“…We show evidence for both increased glycolytic flux and resistance to apoptosis in NCM356 cell overexpressing CBS. H 2 S has also been shown to impact gene expression by altering histone H3 acetylation and DNA methylation (42). Thus, H 2 S-dependent and independent (i.e., increased O-GlcNAc of protein) processes could be responsible for the robust effects of CBS overexpression on NCM356 transcriptome.…”

The role of hydrogen sulfide in aging and age-related pathologies

“…Several studies show epigenetic chromatin modulation by H 2 S [114, 115]. Slow-releasing H 2 S donors inhibit tumor growth both in vitro and in vivo by a combination of cell-cycle arrest and apoptosis promotion, which was related to histone hyperacetylation [116–118].…”

“…Slow-releasing H 2 S donors inhibit tumor growth both in vitro and in vivo by a combination of cell-cycle arrest and apoptosis promotion, which was related to histone hyperacetylation [116–118]. The transcription of pro-inflammatory cytokines, like IL-6 and TNF-α, was altered due to histone modifications and accompanying changes in chromatin structure [114]. Expression and activity of SIRT1 is mediated by H 2 S [10, 119, 120].…”

Atherosclerosis and the Hydrogen Sulfide Signaling Pathway – Therapeutic Approaches to Disease Prevention

“…Besides, H 2 S maintains mtDNA replication and copy number by demethylation of mitochondrial transcription factor A ( TFAM ) [76]. Not limited to DNA itself, H 2 S can also remodel chromatin to modulate cytokine production [77]. Interestingly, CSE gene promoter was methylated by ox-LDL treatment in macrophages and in ApoE KO mice, which was recently reported by Du et al [78].…”