Abstract
Background Previous studies have demonstrated pivotal roles of disintegrin and metalloproteinase 10 (ADAM10) in the pathogenesis of sepsis. MicroRNA- (miR-) 23b has emerged as an anti-inflammatory factor that prevents multiple autoimmune diseases. However, the underlying mechanisms of miR-23b in the regulation of ADAM10 and sepsis remain uncharacterized. Methods The expression levels of ADAM10 and miR-23b were detected by quantitative RT-PCR and western blot analysis. Cytokine production and THP-1 cell apoptosis were measured by enzyme-linked immunosorbent and annexin V apoptosis assays. Bioinformatics analyses and qRT-PCR, western blot, and luciferase reporter assays were performed to identify ADAM10 as the target gene of miR-23b. Results miR-23b expression was downregulated in the peripheral blood mononuclear cells of sepsis patients and LPS-induced THP-1 cells and was negatively correlated with the expression of ADAM10 and inflammatory cytokines. miR-23b regulated ADAM10 expression by directly binding to the 3′-UTR of ADAM10 mRNA. The overexpression of miR-23b alleviated the LPS-stimulated production of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and apoptosis by targeting ADAM10 in THP-1 cells. The inhibitor or knockdown of ADAM10 elicited effects similar to those of miR-23b on THP-1 cells upon LPS stimulation. Conclusions The present study demonstrated that miR-23b negatively regulated LPS-induced inflammatory responses by targeting ADAM10. The molecular regulatory mechanism of miR-23b in ADAM10 expression and sepsis-induced inflammatory consequences may provide potential therapeutic targets for sepsis.
Highlights
Sepsis is defined as a systemic inflammatory reaction syndrome resulting from infection by various pathogenic microorganisms; it results in distressingly high morbidity and mortality in intensive care units (ICUs) throughout the world [1, 2]
Our results showed that LPS significantly increased A disintegrin and metalloproteinase 10 (ADAM10) expression and inflammatory cytokine (TNF-α, IL-1β, and IL-6) production in a time-dependent manner (Figures 1(f)–1(h))
MiR-23b expression in cells was significantly downregulated by LPS treatment in a time-dependent manner; it reached the lowest level at 12 h following challenge with 500 ng/mL LPS. These results indicated that miR-23b might be involved in the regulation of ADAM10 expression and the inflammatory response in THP-1 cells upon LPS stimulation
Summary
Sepsis is defined as a systemic inflammatory reaction syndrome resulting from infection by various pathogenic microorganisms; it results in distressingly high morbidity and mortality in intensive care units (ICUs) throughout the world [1, 2]. The specific antagonist or genomic deletion of ADAM10 contributes to a significant decrease in septic response and endothelial barrier disruption and confers a protective benefit against sepsis to mice [9, 10]. These lines of evidence indicate that the blockade of ADAM10 may be a promising therapeutic target for sepsis. The overexpression of miR-23b alleviated the LPS-stimulated production of inflammatory cytokines (TNF-α, IL-1β, and IL-6) and apoptosis by targeting ADAM10 in THP-1 cells. The present study demonstrated that miR-23b negatively regulated LPS-induced inflammatory responses by targeting ADAM10. The molecular regulatory mechanism of miR-23b in ADAM10 expression and sepsis-induced inflammatory consequences may provide potential therapeutic targets for sepsis
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