1. Bromodomain-Containing 4 Is a Positive Regulator of Interleukin-34 Production in the Gut.
- Author
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Franzè E, Laudisi F, Frascatani R, Tomassini L, De Cristofaro E, Stolfi C, and Monteleone G
- Subjects
- Animals, Humans, Mice, Male, Female, Mice, Inbred C57BL, Intestinal Mucosa metabolism, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Azepines pharmacology, Adult, Middle Aged, Nuclear Proteins metabolism, Nuclear Proteins genetics, Triazoles pharmacology, Dextran Sulfate, Bromodomain Containing Proteins, Interleukins metabolism, Interleukins genetics, Transcription Factors metabolism, Colitis metabolism, Colitis pathology, Colitis chemically induced, Inflammatory Bowel Diseases metabolism, Inflammatory Bowel Diseases pathology, Inflammatory Bowel Diseases genetics
- Abstract
Experimental evidence suggests that, in the inflamed gut of inflammatory bowel disease (IBD) patients, interleukin-34 (IL-34) triggers detrimental signaling pathways. Factors/mechanisms regulating IL-34 production in IBD remain poorly characterized. Bromodomain-containing 4 (BRD4), a transcriptional and epigenetic regulator, is over-expressed in IBD, and studies in cancer cells suggest that BRD4 might positively control IL-34 expression. This study aimed to assess whether, in IBD, BRD4 regulates IL-34 expression. In IBD, there was an up-regulation of both IL-34 and BRD4 compared to the controls, and the two proteins co-localized in both lamina propria mononuclear cells (LPMCs) and epithelial cells. Flow cytometry analysis of CD45+ LPMCs confirmed that the percentages of IL-34- and BRD4-co-expressing cells were significantly higher in IBD than in the controls and showed that more than 80% of the IL-34-positive CD45-LPMCs expressed BRD4. IL-34 and BRD4 were mainly expressed by T cells and macrophages. IL-34 expression was reduced in IBD LPMCs transfected with BRD4 antisense oligonucleotide and in the colons of mice with dextran sulfate sodium-induced colitis treated with JQ1, a pharmacological inhibitor of BRD4. These data indicate that BRD4 is a positive regulator of IL-34 in IBD, further supporting the pathogenic role of BRD4 in IBD-associated mucosal inflammation.
- Published
- 2024
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