Hypoxia activates SUMO-1-HIF-1α signaling pathway to upregulate pro-inflammatory cytokines and permeability in human tonsil epithelial cells

Abstract

Adenoid 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. In this study, with use of a variety of biochemical approaches including gene silencing and transiently ectopic protein expression, we examined the molecular effectors involved in this process in an in vitro model of human tonsil epithelial cells (HTECs). 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 thus preventing its ubiquitination and degradation in HTECs. We also found that activating HIF-1α promoted permeability of HTEC cells as well as production and secretion of a variety of proin ammatory cytokines including IL-6, IL-8, and TNF-α, and pro-angiogenic growth factor VEGF. Furthermore, our data showed that hypoxia-induced in ammation was markedly inhibited by M2 macrophages that possess potent anti-in ammatory function. Our results suggest that selectively inhibiting the SUMO-1-HIF-1α signaling pathway leads to in ammatory responses in human tonsil epithelial cells, which might be a novel therapeutic approach for managing hypoxia-induced SDB resulting from AH.

Mild Hypothermia Promotes Ischemic Tolerance and Survival of Neural Stem Cell Grafts by Enhancing Global SUMOylation

“…According to previous studies, we speculate that hypoxia greatly increases SUMO modification levels of numerous target proteins, including HIF-1α, Oct4, and SOX2. Theoretically, SUMO-modified HIF-1α, Oct4, and SOX2 cannot be degraded by ubiquitin hydrolase [23][24][25], thus allowing these proteins to persist and stably exist in the nucleus and cytoplasm of NSCs, whereby they increase hypoxia tolerance and stemness potential.…”

Adenotonsillectomy-related changes in systemic inflammation among children with obstructive sleep apnea

“…In addition, hypoxia has been shown to activate the SUMO-1-HIF-1α signaling pathway to upregulate the production of IL-8 and permeability in human tonsil epithelial cells. 43 After total excision of the tonsils in our patients, % change in IL-8 was positively correlated with change in tonsil size (ie, the larger the preoperative tonsil size, the greater the postoperative reduction in the IL-8 serum level), suggesting that a hypertrophic tonsil is the primary origin of IL-8 production. Moreover, although previous studies have reported a higher concentration of IL-8 in OSA patients and that this may contribute to weight gain 44 and % body fat, 45 we found that % change in IL-8 after adenotonsillectomy was not related to % change in AHI or % change in BMI z-score.…”

Distribution of serum uric acid concentration and its association with lipid profiles: a single-center retrospective study in children aged 3 to 12 years with adenoid and tonsillar hypertrophy

“…Compared to healthy children, children with chronic adenoid and tonsillar hypertrophy were under significant oxidative stress and had significantly increased levels of proinflammatory cytokines [ 29 , 30 ]. Chronic and recurrent adenoid and tonsillar hypertrophy could cause harmful effects on untreated children, including upper airway obstruction, chronic intermittent hypoxia and sleep-disordered breathing [ 31 ]. As a marker of hypoxic stress, the UA concentration is associated with inflammatory stimulation [ 32 , 33 ].…”