Fundamental role for HIF-1α in constitutive expression of human β defensin-1

Kelly, Caleb; Glover, Louise; Campbell, Eric L.; Kominsky, Douglas J.; Ehrentraut, Stefan; Bowers, Brittelle; Bayless, Amanda J.; Saeedi, Bejan; Colgan, Sean P.

doi:10.1038/mi.2013.6

Cited by 121 publications

(119 citation statements)

References 39 publications

(47 reference statements)

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“…Human β defensin-1 (hBD1) is notable within the intestinal epithelium because it is constitutively secreted, whereas other antimicrobial peptides are induced by inflammatory mediators (8). Constitutive expression of hBD1 depended on basal HIF-1α signaling in multiple IEC lines and hBD1 expression correlated with other HIF target genes in human tissues (12). Another distinguishing feature of hBD1 is that the full spectrum of its antimicrobial activity is only revealed when its disulfide bonds are reduced (57).…”

Section: Molecular Aspects Of Barrier Regulation In the Mucosamentioning

confidence: 99%

“…First, in the normal GI mucosa, particularly in the colon, physiologic hypoxia predominates (7). These studies have shown that these low pO 2 conditions are critical for the constitutive expression of some innate immune factors (12) and certain epithelial tight junction proteins (13) (discussed below). Second, inflammatory lesions observed in models of colitis are profoundly hypoxic (or even anoxic), with pO 2 levels that are comparable to the pO 2 levels observed in some large tumors (7).…”

Section: Oxygen Utilization In the Mucosamentioning

confidence: 99%

See 1 more Smart Citation

Oxygen metabolism and barrier regulation in the intestinal mucosa

Glover¹,

Lee²,

Colgan³

2016

Journal of Clinical Investigation

136

108

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Section: Molecular Aspects Of Barrier Regulation In the Mucosamentioning

confidence: 99%

Section: Oxygen Utilization In the Mucosamentioning

confidence: 99%

Oxygen metabolism and barrier regulation in the intestinal mucosa

Glover¹,

Lee²,

Colgan³

2016

Journal of Clinical Investigation

136

108

View full text Add to dashboard Cite

“…21 HIF-1a regulates basal defensin expression in intestinal epithelial cells and is protective in murine experimental colitis. 22,23 The epithelial surfaces of the respiratory tract are continuously exposed to microbes. Innate and adaptive immune functions of diverse cell types such as resident alveolar macrophages, epithelial cells and dendritic cells are required to prevent and control infections of the lung.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia and the hypoxia-regulated transcription factor HIF-1α suppress the host defence of airway epithelial cells

et al. 2017

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Chronic diseases of the respiratory tract, such as cystic fibrosis, are associated with mucosal and systemic hypoxia. Innate immune functions of airway epithelial cells are required to prevent and control infections of the lung parenchyma. The transcription factor hypoxia-inducible factor 1a (HIF-1a) regulates cellular adaptation to low oxygen conditions. Here, we show that hypoxia and HIF-1a regulate innate immune mechanisms of cultured human bronchial epithelial cells (HBECs). Exposure of primary HBECs to hypoxia or the prolyl hydroxylase inhibitor dimethyloxaloylglycine (DMOG) resulted in a significantly decreased expression of inflammatory mediators (IL-6, IFN-g-induced protein 10) in response to ligands for TLRs (flagellin, polyI:C) and Pseudomonas aeruginosa, whereas the expression of inflammatory mediators was not affected by hypoxia or DMOG in the absence of microbial factors. Small interfering RNA-mediated knockdown of HIF-1a in HBECs and in the bronchial epithelial cell line Calu-3 resulted in increased expression of inflammatory mediators. The inflammatory response was decreased in lungs of mice stimulated with inactivated P. aeruginosa under hypoxia. These data suggest that hypoxia suppresses the innate immune response of airway epithelial cells via HIF-1a.

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“…Hypoxia has been reported to increase ITF and HBD expression in intestinal epithelial cells in previous studies; Furuta interpreted this process as the mechanism for maintenance of barrier function when oxygen levels are low 30,31 . Xu et al, demonstrated that ITF expression in the intestines of rats exposed to intrauterine asphyxia increased 72 h after birth 32 , followed by rapid proliferation of the mucosa with the recovery of intestinal function.…”

Section: Discussionmentioning

confidence: 99%

Untitled

2017

IJPSR

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Perinatal hypoxia results in poor circulation in internal organs, causing damage to the intestinal mucosa. Here, we aimed to evaluate the role of endothelial vasoconstrictor function in the formation of the intestinal mucous barrier in low-birth-weight neonates with hypoxicischemic encephalopathy (HIE). We comparatively analysed the concentrations of specific intestinal protective markers, i.e., serum mucin 2 (MUC2), serum intestinal trefoil factor (ITF), and faecal human β-defensin 2 (HBD2), and a marker of endothelial activity, i.e., serum endothelin-1 (ET-1), in early of postnatal life in 8 infants with moderate/severe HIE (group 1), 14 neonates with mild HIE (group 2), and 20 control infants using standard enzyme-linked immunosorbent assays. Markers of intestinal mucosa activity were not differentially expressed between infants in groups 1 and 2. Mean total concentrations of ITF and HBD2 were higher in groups 1 and 2 than in the control group (p < 0.05). In contrast, MUC2 concentrations were lower in infants of groups 1 and 2 than in the control infants. ET-1 expression was higher in group 2 than in group 1 and the control group on days 1-3 (p < 0.05). Spearman's rank-order correlation analysis showed that there were no significant relationships of ET-1 with MUC2 and HBD2. However, there was a significant negative correlation between ET-1 and ITF in group 1 infants. High serum ITF and faeces HBD2 levels accompanied low blood concentrations of MUC2, reflecting the depletion of Goblet cell function in response to hypoperfusion in low-birth-weight infants with HIE.

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Fundamental role for HIF-1α in constitutive expression of human β defensin-1

Cited by 121 publications

References 39 publications

Oxygen metabolism and barrier regulation in the intestinal mucosa

Oxygen metabolism and barrier regulation in the intestinal mucosa

Hypoxia and the hypoxia-regulated transcription factor HIF-1α suppress the host defence of airway epithelial cells

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