Dual transcriptome sequencing reveals resistance of TLR4 ligand-activated bone marrow-derived macrophages to inflammation mediated by the BET inhibitor JQ1

Abstract

Persistent macrophage activation is associated with the expression of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify inflammatory disorders. A novel synthetic BET inhibitor, JQ1, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for JQ1 molecular targets has not been undertaken. The present study aimed at evaluating the anti-inflammatory function and underlying genes that are targeted by JQ1 in LPS-stimulated primary bone marrow-derived macrophages (BMDMs) using global transcriptomic RNA sequencing and quantitative real-time PCR. Among the annotated genes, transcriptional sequencing of BMDMs that were treated with JQ1 revealed a selective effect on LPS-induced gene expression in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent (transcription factors) TFs was suppressed. Additionally, we found that JQ1 reduced the expression of previously unidentified genes that are important in inflammation. Importantly, these inflammatory genes were not affected by JQ1 treatment alone. Furthermore, we confirmed that JQ1 reduced cytokines/chemokines in the supernatants of LPS treated BMDMs. Moreover, the biological pathways and gene ontology of the differentially expressed genes were determined in the JQ1 treatment of BMDMs. These unprecedented results suggest that the BET inhibitor JQ1 is a candidate for the prevention or therapeutic treatment of inflammatory disorders.

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

“…To date, few studies have described the autophagy‐modulating role of BRD4 inhibition in tumour cells . One such study reported that glioma cells treated with JQ1 exhibited increased autophagic activity . In imatinib‐resistant GIST cells, increased expression of LC3‐II, a widely accepted autophagic marker, was inducible by JQ1, and its level was even higher upon combined treatment with JQ1 and imatinib.…”

“…44 One such study reported that glioma cells treated with JQ1 exhibited increased autophagic activity. [45][46][47] In imatinib-resistant GIST cells, increased expression of LC3-II, a widely accepted autophagic marker, was inducible by JQ1, and its level was even higher upon combined treatment with JQ1 and imatinib. Although AKT-inactivation-induced apoptosis directs cells to programmed death, the significance of BRD4-inhibitioninduced autophagy in GIST requires further elucidation.…”

The citrus flavonoid naringenin confers protection in a murine endotoxaemia model through AMPK-ATF3-dependent negative regulation of the TLR4 signalling pathway

“…Then, peritoneal macrophages were plated in plates or dishes and cultured at 37 °C in a humidified incubator supplemented with 5% CO2. Murine bone marrow-derived macrophages (BMDMs) were isolated from the femurs of BALB/c mice and differentiated by supplementing with 50 ng/ml m-CSF for 3–5 days40. Primary macrophages or murine macrophage such as RAW 264.7 cells (ATCC, Manassas, VA, USA) were cultured in high-glucose DMEM supplemented with 10% FBS at 37 °C in a 5% CO2 humidified incubator.…”

BRD4 inhibition attenuates inflammatory response in microglia and facilitates recovery after spinal cord injury in rats

“…To the best of our knowledge, this is the first study exploring the role of BRD4 in inflammatory response regulation after SCI and describing a BRD4 inhibitor capable of suppressing inflammatory response via negatively modulating NF-κB and MAPK signalling pathways (Figure 8).BET family such as BRD4 are reported to activate many inflammation-related genes,26 and inflammation blocks functional recovery and aggravates neuropathic paresthesia in damaged spinal cord 27,28. To the best of our knowledge, this is the first study exploring the role of BRD4 in inflammatory response regulation after SCI and describing a BRD4 inhibitor capable of suppressing inflammatory response via negatively modulating NF-κB and MAPK signalling pathways (Figure 8).BET family such as BRD4 are reported to activate many inflammation-related genes,26 and inflammation blocks functional recovery and aggravates neuropathic paresthesia in damaged spinal cord 27,28.…”