Abstract
BackgroundAdenoid hypertrophy (AH) can cause harmful effects on untreated children, which include mouth breathing, chronic intermittent hypoxia, sleep disordered breathing (SDB), and even some behavioral problems. However, the molecular mechanisms underlying this pathophysiological process have remained poorly understood. MethodsIn this study, SUMO was induced silencing and overexpression using RNAi and lentiviral-mediated vector. FITC-Dextran and TEER were performed to examine the role of SUMO in cell permeability. Co-immunoprecipitation (Co-IP) assay was performed to examine the interaction between SUMO1 and HIF-1α. Immunohistochemistry staining was used to examine the expressions of ZO-1, Claudin-1 and occluding respectively. ResultsWe found that a hypoxic condition caused a dramatic upregulation of SUMO-1 expression in a time-dependent manner, a member of the ubiquitin-like protein family. Knockdown of SUMO-1 deeply suppressed the secretions of pro-inflammation cytokines including IL-6, IL-8, and TNF-α, and decreased the permeability of HTECs. Moreover, the HIF-1α inhibitor 2-MeOE2 abolished the function of SUMO-1 in HTECs. Furthermore, results obtained from CO-IP had suggested that SUMO-1 interacted with HIF-1α, and prevented its ubiquitination and degradation in HTECs by sumoylating. Importantly, our data showed that hypoxia-induced inflammation was markedly inhibited by M2 macrophages that possess potent anti-inflammatory function. ConclusionOur results suggest that selectively inhibiting the SUMO-1-HIF-1α signaling pathway leads to anti-inflammatory responses in human tonsil epithelial cells, which might be a novel therapeutic approach for managing hypoxia-induced SDB resulting from AH.
Highlights
Adenoid hypertrophy (AH) has been long considered as the most common cause of nasopharyngeal obstruction in children [17]
We found that a hypoxic condition caused a dramatic upregulation of SUMO-1 expression, a member of the ubiquitin-like protein family, which in turn stabilized hypoxia-inducible factor (HIF)-1α by sumoylating this HIF subunit and preventing its ubiquitination and degradation in human tonsil epithelial cells (HTECs)
Our results suggest that selectively inhibiting the SUMO-1-HIF-1α signaling pathway leads to inflammatory responses in human tonsil epithelial cells, which might be a novel therapeutic approach for managing hypoxia-induced sleep disordered breathing (SDB) resulting from AH
Summary
Adenoid hypertrophy (AH) has been long considered as the most common cause of nasopharyngeal obstruction in children [17]. Eukaryotic cells have established an intrinsic and rapid oxygen-sensing system, known as hypoxia-inducible factors (HIFs), to facilitate hypoxic responses via HIF stabilization [25, 26] This system has been demonstrated to induce expression of more than 100 downstream target genes, thereby enhancing the oxygen supply and supporting anaerobic ATP generation [30]. The oxygen-requiring PHD and factor inhibiting HIF-1α (FIH) are inactivated, which leads to nuclear translocation of HIF-1α and activation of its target genes. Sumoylation is another common form of post-translational modification affecting the transcriptional activity of numerous transcription factors [7, 31, 13]. A previous study has demonstrated that SUMO-1-mediated modification at Lys391/Lys477 residues of HIF-1α can significantly enhance this subunit’s stability as well as transcriptional activity [3]
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