Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by inflammatory injury to the alveolar and capillary barriers that results in impaired gas exchange and severe acute respiratory failure. Nuclear orphan receptor Nur77 has emerged as a regulator of gene expression in inflammation, and its role in the pathogenesis of ARDS is not clear. The objective of this study is to investigate the potential role of Nur77 and its underlying mechanism in the regulation of endothelin-1 (ET-1) expression in lipopolysaccharide (LPS)-induced A549 cells and an ARDS rat model. We demonstrate that LPS induced Nur77 expression and nuclear export in A549 cells. Overexpression of Nur77 markedly decreased basal and LPS-induced ET-1 expression in A549 cells, whereas knockdown of Nur77 increased the ET-1 expression. LPS-induced phosphorylation and nuclear translocation of NF-κB and p38 MAPK were blocked by Nur77 overexpression and augmented by Nur77 knockdown in A549 cells. In vivo, LPS induced Nur77 expression in lung in ARDS rats. Pharmacological activation of Nur77 by cytosporone B (CsnB) inhibited ET-1 expression in ARDS rats, decreased LPS-induced phosphorylation of NF-κB and p38 MAPK, and relieved lung, liver, and kidney injury. Pharmacological deactivation of Nur77 by 1,1-bis-(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH, C-DIM8) had no effect on ET-1 expression and lung injury. These results indicated that Nur77 decreases ET-1 expression by suppressing NF-κB and p38 MAPK in LPS-stimulated A549 cells in vitro, and, in an LPS-induced ARDS rat model, CsnB reduced ET-1 expression and lung injury in ARDS rats.

Protective effects of resveratrol on osteoporosis via activation of the SIRT1‑NF‑κB signaling pathway in rats

“…The sirtuin 1 (SIRT1) protein was the first member of the Sirtuin protein family to be discovered (5). It has been reported that enzymes associated with SIRT1 are class III histone acetylation enzymes dependent on nicotinamide adenine dinucleotide (NAD + ), which is highly conserved (6).…”

Cigarette smoke downregulates Nur77 to exacerbate inflammation in chronic obstructive pulmonary disease (COPD)

“…Nur77 deficiency exacerbated OVA-induced allergic airway inflammation in mice [26]. Also, Nur77 expression limited LPS-induced inflammation and tissue damage in a rat model of acute respiratory distress syndrome [27]. Nur77 was identified as a potential modulator of pulmonary arterial hypertension, as its expression was downregulated in lungs of patients with pulmonary arterial hypertension and also in cultured pulmonary microvascular endothelial cells [36].…”

From sepsis to acute respiratory distress syndrome (ARDS): emerging preventive strategies based on molecular and genetic researches

“…Mitogen-activated protein kinase (MAPK) signal MAPK signaling is suppressed by blocking the phosphorylation of JNK and p38, which decreases the levels of the pro-inflammatory cytokines IL-6 and TNF-α and increases the level of the anti-inflammatory cytokine IL-10 to subsequently alleviate the inflammation in subjects with sepsis-induced ARDS [54].…”

“…At the transcriptional level, several studies have postulated an interaction between the nuclear orphan receptor and endothelin-1 (ET-1). As a negative regulator, Nur77 is activated by cytosporone B (CsnB) and suppresses ET-1 expression by decreasing the lipopolysaccharide (LPS)-induced phosphorylation of NF-κβ p65 and p38 MAPK, which relieved lung injury in a mouse model of ARDS [54]. Furthermore, in vascular endothelial cells, 6-mercaptopurine (6-MP) also activates Nur77and subsequently decreases ET-1 expression by inhibiting AP-1-dependent c-Jun promoter activity [55].…”