Bromodomain-containing 4 is a Positive Regulator of the Inflammatory Cytokine Response in the Gut

Abstract

Abstract Background and Aim Bromodomain-containing protein 4 [BRD4], one of the components of the bromodomain and extraterminal domain [BET] family, is a transcriptional and epigenetic regulator of cellular proliferation and cytokine production. In this study, we assessed whether BRD4 regulates the cytokine response in inflammatory bowel diseases [IBD]. Materials and Methods BRD4 expression was analysed in intestinal mucosal samples of patients with ulcerative colitis [UC], patients with Crohn’s disease [CD], normal controls [CTRs], and mice with chemically-induced colitis, by real-time polymerase chain reaction [PCR], western blotting, and confocal microscopy. Cytokine production was evaluated in lamina propria mononuclear cells [LPMCs] of IBD patients and mucosal tissues of colitic mice treated with BRD4 inhibitors. Finally, we evaluated the effect of JQ1, an inhibitor of the BRD4 signalling pathway, on the course of murine colitis. Results BRD4 RNA and protein expression was up-regulated in the inflamed mucosa of patients with UC and patients with CD as compared with the uninvolved areas of the same patients and CTRs, and in the inflamed colon of colitic mice. Knockdown of BRD4 with a specific antisense oligonucleotide in IBD LPMCs led to reduced expression of TNF-α, IL-6, IFN-γ, and IL-17A. Administration of JQ1 to colitic mice inhibited the inflammatory cytokine response and attenuated the ongoing colitis. Conclusions This is the first study showing the up-regulation of BRD4 in IBD and suggesting the role of such a protein in the positive control of the inflammatory cytokine response in the gut.