title: Human adipocytes are highly sensitive to intermittent hypoxia induced NF-kappaB activity and subsequent inflammatory gene expression.
abstract: BACKGROUND
  Intermittent hypoxia (IH)-induced activation of pro-inflammatory pathways is a major contributing factor to the cardiovascular pathophysiology associated with obstructive sleep apnea (OSA). Obesity is commonly associated with OSA although it remains unknown whether adipose tissue is a major source of inflammatory mediators in response to IH. The aim of this study was to test the hypothesis that IH leads to augmented inflammatory responses in human adipocytes when compared to cells of non-adipocyte lineages.
  
  
  RESULTS
  Human primary subcutaneous and visceral adipocytes, human primary microvascular pulmonary endothelial cells (HUMEC-L) and human primary small airway epithelial cells (SAEC) were exposed to 0, 6 or 12 cycles of IH or stimulated with tumor necrosis factor (TNF)-α. IH led to a robust increase in NF-κB DNA-binding activity in adipocytes compared with normoxic controls regardless of whether the source of adipocytes was visceral or subcutaneous. Notably, the NF-κB response of adipocytes to both IH and TNF-α was significantly greater than that in HUMEC-L and SAEC. Western blotting confirmed enhanced nuclear translocation of p65 in adipocytes in response to IH, accompanied by phosphorylation of I-κB. Parallel to p65 activation, we observed a significant increase in secretion of the adipokines interleukin (IL)-8, IL-6 and TNF-α with IH in adipocytes accompanied by significant upregulation of mRNA expression. PCR-array suggested profound influence of IH on pro-inflammatory gene expression in adipocytes.
  
  
  CONCLUSIONS
  Human adipocytes demonstrate strong sensitivity to inflammatory gene expression in response to acute IH and hence, adipose tissue may be a key source of inflammatory mediators in OSA.
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland.
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland; Pulmonary and Sleep Disorders Unit, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Kent
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland; Pulmonary and Sleep Disorders Unit, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Sophie J
authors.initials: SJ
authors.lastname: Crinion
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland; Pulmonary and Sleep Disorders Unit, St. Vincent's University Hospital, Dublin, Ireland.
authors.forename: Walter T
authors.initials: WT
authors.lastname: McNicholas
authors.affiliation: School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland; Pulmonary and Sleep Disorders Unit, St. Vincent's University Hospital, Dublin, Ireland. Electronic address: silke.ryan@ucd.ie.
authors.forename: Silke
authors.initials: S
authors.lastname: Ryan
mesh_terms: D021581:Active Transport, Cell Nucleus; D052438:Adipocytes, White / Q000378:metabolism*; D054392:Adipokines / Q000235:genetics / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics* / Q000502:physiology*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D054392:Adipokines; C508606:CXCL8 protein, human; D020672:I-kappa B Proteins; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; C498143:RELA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004247:DNA
keywords: Adipocytes; Inflammation; Intermittent hypoxia; Obstructive sleep apnea