Abstract
Simple SummaryEpigenetic modifications of the genes regulate the inflammation process that includes the DNA methylation and histone acetylation. Sulforaphane is well known for its immunomodulatory properties. Notably, the mechanism of its anti-inflammatory functions involving epigenetic modifications is unclear. This study highlighted the regulatory mechanism of sulforaphane in the innate immunity responses in an acute inflammatory state employ in vivo cell culture model. Porcine monocyte-derived dendritic cells were exposed to LPS with or without sulforaphane pre-treatment for these purposes. Epigenetics modulations of the important genes and regulatory factors were studies as well as the immune responses of the cells were vigorously studied over the period of time. This study deciphers the mechanism of SFN in restricting the excessive inflammatory reactions, thereby, exerting its protective and anti-inflammatory function though epigenetic mechanism.Inflammation is regulated by epigenetic modifications, including DNA methylation and histone acetylation. Sulforaphane (SFN), a histone deacetylase (HDAC) inhibitor, is also a potent immunomodulatory agent, but its anti-inflammatory functions through epigenetic modifications remain unclear. Therefore, this study aimed to investigate the epigenetic effects of SFN in maintaining the immunomodulatory homeostasis of innate immunity during acute inflammation. For this purpose, SFN-induced epigenetic changes and expression levels of immune-related genes in response to lipopolysaccharide (LPS) stimulation of monocyte-derived dendritic cells (moDCs) were analyzed. These results demonstrated that SFN inhibited HDAC activity and caused histone H3 and H4 acetylation. SFN treatment also induced DNA demethylation in the promoter region of the MHC-SLA1 gene, resulting in the upregulation of Toll-like receptor 4 (TLR4), MHC-SLA1, and inflammatory cytokines’ expression at 6 h of LPS stimulation. Moreover, the protein levels of cytokines in the cell culture supernatants were significantly inhibited by SFN pre-treatment followed by LPS stimulation in a time-dependent manner, suggesting that inhibition of HDAC activity and DNA methylation by SFN may restrict the excessive inflammatory cytokine availability in the extracellular environment. We postulate that SFN may exert a protective and anti-inflammatory function by epigenetically influencing signaling pathways in experimental conditions employing porcine moDCs.
Highlights
The innate immune system is the first line of defense against invading pathogens.In order to detect a microbial attack, the host relies on sentinel cells, such as dendritic cells (DCs) and macrophages
The results showed that pre-incubation of monocyte-derived dendritic cells (moDCs) with SFN remarkably suppressed LPS-induced inhibition of histone deacetylase (HDAC) activity (Figure 1A)
The present study has shown that the HDAC inhibitor SFN has an essential role in the Tempera‐Amplicon acetylation of histone and non-histone proteins during the regulation ofGenBank the inflammatory
Summary
The innate immune system is the first line of defense against invading pathogens.In order to detect a microbial attack, the host relies on sentinel cells, such as dendritic cells (DCs) and macrophages. The innate immune system is the first line of defense against invading pathogens. DCs are specialized antigen-presenting cells (APCs) that are involved in regulating immune responses [1]. The recognition and presentation of invasive pathogens by DCs are triggered by microbe-specific motifs known as pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) in the case of Gram-negative bacteria [2,3]. TLR4 is proven to be an important sensor for LPS [3]. LPS-activated TLR4 triggers the mitogenactivated protein kinase (MAPK), nuclear factor-κB (NF-κB), and interferon-related factor (IRF) signaling transduction pathways [4]. The transcription of immune genes is induced, including cytokines, which are critical for the activation of innate and adaptive immunity and controlling the inflammatory process [4]
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