(+)-JQ1 attenuated LPS-induced microglial inflammation via MAPK/NFκB signaling

Abstract

BackgroundMicroglia activation is a crucial event in neurodegenerative disease. The depression of microglial inflammatory response is considered a promising therapeutic strategy. NFκB signaling, including IKK/IκB phosphotylation, p65 nucelus relocalization and NFκB-related genes transcription are prevalent accepted to play important role in microglial activation. (+)-JQ1, a BRD4 inhibitor firstly discovered as an anti-tumor agent, was later confirmed to be an anti-inflammatory compound. However, its anti-inflammatory effect in microglia and central neural system remains unclear.ResultsIn the current work, microglial BV2 cells were applied and treatment with lipopolysaccharide (LPS) to induce inflammation and later administered with (+)-JQ1. In parallel, LPS and (+)-JQ1 was intracerebroventricular injected in IL-1β-luc transgenic mice, followed by fluorescence evaluation and brain tissue collection. Results showed that (+)-JQ1 treatment could significantly reduce LPS induced transcription of inflammatory cytokines both in vitro and in vivo. (+)-JQ1 could inhibit LPS induced MAPK but not PI3K signaling phosphorylation, NFκB relocalization and transcription activity. In animal experiments, (+)-JQ1 postponed LPS induced microglial and astrocytes activation, which was also dependent on MAPK/NFκB signaling.ConclusionsThus, our data demonstrated that (+)-JQ1 could inhibit LPS induced microglia associated neuroinflammation, via the attenuation of MAPK/NFκB signaling.

A chemical conjugation of JQ‐1 and a TLR7 agonist induces tumoricidal effects in a murine model of melanoma via enhanced immunomodulation

“…We initially examined the immunostimulatory activity of combined usage of SZU‐101 and JQ‐1, and found that JQ‐1 strongly repressed the production of cytokines induced by SZU‐101 in vitro. None of the cytokines could be detected in the Combo group (Figure 1B), which was consistent with the previous report that JQ‐1 attenuated LPS‐induced transcription of inflammatory cytokines via MAPK/NF‐κB signaling 27 . Interestingly, we synthesized a novel compound (SZU‐119) by chemical conjugation of SZU‐101 and JQ‐1, with better effects on cytokine release than the simple commixture of SZU‐101 and JQ‐1.…”

“…None of the cytokines could be detected in the Combo group ( Figure 1B), which was consistent with the previous report that JQ-1 attenuated LPSinduced transcription of inflammatory cytokines via MAPK/NF-κB signaling. 27 Interestingly, we synthesized a novel compound (SZU-119) by chemical conjugation of SZU-101 and JQ-1, with better effects on cytokine release than the simple commixture of SZU-101 and JQ-1.…”

BRD4 inhibition regulates MAPK, NF‐κB signals, and autophagy to suppress MMP‐13 expression in diabetic intervertebral disc degeneration

“…Based on the results of the regulatory effects of BRD4 on 3 important factors as described above, a possibility exists that BRD4 might regulate MMP-13 in diabetic condition (35,38,39). In this study, we found that BRD4 knockdown resulted in decreased MMP-13 level under AGEs-BSA-induced diabetic stress, which was coincident with the effect of JQ1 on MMP-13 in NPCs.…”

Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD

“…Mitogen-activated protein kinase (MAPK) signaling plays an important role in LPS-and/or Aβ-induced proinflammatory cytokine levels. In addition, MAPK signaling is markedly increased in LPS-treated microglial cells and astrocytes in vitro and in vivo (i.e., ERK, AKT) [27]. Importantly, several tyrosine kinase inhibitors alter LPS and Aβ-mediated MAPK signaling to modulate neuroinflammatory responses.…”