Abstract
High mobility group box 1 (HMGB1) is a prototypic alarmin and plays an important role in the pathogenesis of inflammatory process in spontaneous preterm birth. This study was conducted to compare the levels of HMGB1 in amniotic fluid and amnion membranes in women with chorioamnionitis/intra-amniotic inflammation to the levels in healthy controls. We also aimed to elucidate the involvement of microRNA-548 (miR-548) in regulating HMGB1 expression and its function in human amniotic epithelial cells (hAECs). A bioinformatics analysis predicted the binding of HMGB1 by the miR-548 cluster. A repressed and forced expression assay in hAECs was performed to investigate the causal relationship between the miR-548 cluster and HMGB1. The levels of HMGB1 in amniotic fluid and amnion membranes were significantly higher in patients with intra-amniotic inflammation/chorioamnionitis than in those without inflammation. The miR-548 was significantly under-expressed in amnion membranes from patients with chorioamnionitis than in normal term controls. Repressed expression of miR-548 up-regulated HMGB1 expression in hAECs and increased its release from hAECs. Moreover, forced expression of miR-548 suppressed HMGB1 and inflammatory cytokines in hAECs, which increased when treated with lipopolysaccharide. These results suggest miR-548 can alter the inflammatory responses in hAECs, and might be involved in the pathogenesis of preterm birth by regulating HMGB1.
Highlights
High mobility group box 1 (HMGB1) is a prototypic alarmin and plays an important role in the pathogenesis of inflammatory process in spontaneous preterm birth
We analyzed HMGB1 levels in amniotic fluid (AF) obtained from women with signs or symptoms of preterm birth who had amniocentesis to rule out infection (n = 38) or for either genetic indication (n = 10)
To validate the correlation between HMGB1 and the miR-548 cluster in patients with preterm birth and acute chorioamnionitis, we investigated whether the expression level of the miR-548 cluster is crucial to the HMGB1 expression level using the synthetic mimics and inhibitors for the miR-548 cluster (Table 3) in human amniotic epithelial cells (hAECs)
Summary
High mobility group box 1 (HMGB1) is a prototypic alarmin and plays an important role in the pathogenesis of inflammatory process in spontaneous preterm birth. Forced expression of miR-548 suppressed HMGB1 and inflammatory cytokines in hAECs, which increased when treated with lipopolysaccharide These results suggest miR-548 can alter the inflammatory responses in hAECs, and might be involved in the pathogenesis of preterm birth by regulating HMGB1. Of the differentially expressed miRNAs in preterm birth groups, the miR-548 cluster and miR-302b were predicted to bind HMGB1 3′UTR by a bioinformatics analysis. We performed this study to (1) compare the levels of HMGB1 in amniotic fluid of patients with intra-amniotic inflammation to those in healthy controls, (2) compare HMGB1 expression in amnion membrane of patients with preterm birth and chorioamnionitis to normal term controls, and (3) investigate the expression of the miR-548 cluster in amnion membrane and explore the regulation of HMGB1 expression by the miR-548 cluster
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