The HDAC Inhibitor, SAHA, Prevents Colonic Inflammation by Suppressing Pro-inflammatory Cytokines and Chemokines in DSS-induced Colitis

Abstract

Inflammatory bowel disease (IBD) is an inflammatory disorder of the gastrointestinal tract that is caused by multiple factors, including dysfunction of the immune system and genetic and epigenetic alterations. Aberrant epigenetic regulation, especially histone acetylation, was found in biopsies from IBD patients and mouse models of colitis, suggesting that an epigenetic treatment approach may be useful for IBD therapy. Therefore, we investigated the effects of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), in a mouse model of dextran sulfate sodium (DSS)-induced colitis. C57BL/6 mice were treated with 1.5% DSS for 5 days and/or SAHA (25 mg/kg BW/day) for 26 days. Levels of mRNA for the pro-inflammatory cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and the chemokines, Ccl2, were examined by qRT-PCR. CD11b, a marker of dendritic cells, macrophages, and monocytes, as well as Ccl2 expression, were examined by immunohistochemistry. IL-6, TNF-α, and Ccl2 gene expression peaked on day 5 in DSS-treated mouse colon, whereas SAHA treatment significantly decreased pro-inflammatory gene expression. Ccl2 protein expression resembled Ccl2 gene expression results. Moreover, localization of CD11b showed that migratory inflammatory cells were dramatically decreased by SAHA treatment compared to DSS-treated mouse colon. Thus, we conclude that the HDAC inhibitor, SAHA, attenuates inflammatory changes in DSS-induced colitis by suppressing local secretion of pro-inflammatory cytokines and chemokines and also by suppressing mobilization and accumulation of inflammatory cells.

Histone Deacetylases Enhance Ca2+-Activated K+ Channel KCa3.1 Expression in Murine Inflammatory CD4+ T Cells

“…The application of HDACis to the treatment of various types of disorders, including immunological and inflammatory disorders, is currently being investigated. The administration of broad-acting HDACis, such as vorinostat, meliorated intestinal inflammation by down-regulating inflammatory cytokines, including IFN-γ, in the CD4 + T cells of IBD model mice and suppressing their mobilization and accumulation [ 22 , 23 ]. Significant elevations in histone acetylation have been observed in the inflamed mucosa of IBD models and inflamed biopsies from patients with Crohn’s disease (CD) [ 24 ].…”

Histone deacetylase inhibition by gut microbe-generated short chain fatty acids entrains intestinal epithelial circadian rhythms

“…With these findings we illuminate a novel mechanism by which the gut microbiota plays a role in maintaining and altering intestinal circadian rhythms. SCFAs and HDACis have been used for their anti-tumor and anti-inflammatory properties and for ameliorating conditions such as diversion colitis 53 and inflammation in mouse models of DSS colitis 54,53,55,56 . Others have shown depletion of colonic SCFAs increases susceptibility to colitis 57 .…”

Antioxidant Traits and Protective Impact of Vorinostat against Cisplatin Induced Hepatoxicity in Rats

“…The hepatotoxicity of CDDP is the major side effect of this drug which occurred during high doses treatment The present study sheds light on the possible protective effects of VST on CDDP hepatotoxicity in male Wistar rats. Recently, VST has been recognized to have antioxidant and anti-inflammatory efficacy both in in vivo models [13]. A low dose of VST has a hepatoprotective effect against drug induced liver damage [14].…”

“…Suberoylanilide hydroxamic acid (SAHA), is an HDAC inhibitor known as vorinostat (VST), was the first HDAC inhibitor approved by the food and drug administration (FDA) to treat certain cutaneous T-cell lymphoma [12]. It has been shown that VST with a low dose can enhance liver function and reduce liver fibrosis [13]. However, the mechanism of action behind that is still not clear.…”