title: Influence of intermittent hypoxia on the signal transduction pathways to inflammatory response and circadian clock regulation.
abstract: OBJECTIVE
  Obstructive sleep apnea syndrome (OSAS), characterized by intermittent hypoxia/reoxygenation (IHR), is often associated with changing levels of circulating inflammatory cytokines and causes excessive daytime sleepiness, mood disturbances, and cardiovascular disease. An abnormal rhythm in the expression of circadian clock genes is observed in OSAS patients, and is also implicated in OSAS-related clinical symptoms. IHR-induced signal transduction is thought to underlie OSAS-associated complications. The aim of this study is to elucidate the influence of IHR on signal transduction pathways to inflammatory response and circadian clock regulation.
  
  
  METHODS
  To evaluate the direct action of IHR on intracellular signaling, we used a cell culture model to explore the underlying transcriptional events initiated by IHR.
  
  
  RESULTS
  Treatment of cultured human lung adenocarcinoma epithelial cells (A549) with IHR resulted in the elevation of mRNA levels of an inflammation cytokine interleukin-6 (IL-6), due to activation of the signaling pathway of nuclear factor-kappaB, a potent transcriptional activator of IL-6. On the other hand, the treatment of cells with IHR had little effect on clock gene response element-driven transcription. As a consequence, there was no significant change in mRNA levels of clock genes in IHR-treated cells.
  
  
  CONCLUSIONS
  These results suggest that IHR can activate signal transduction to an inflammatory response, but not to circadian clock regulation. The abnormal rhythm in the expression of clock genes in OSAS patients is attributable to the changed levels of circulating factors that have the ability to modulate clock gene expression.
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago 683-8504, Japan. burioka@grape.med.tottori-u.ac.jp
authors.forename: Naoto
authors.initials: N
authors.lastname: Burioka
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fukuoka
authors.forename: Fumiyasu
authors.initials: F
authors.lastname: Okazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujioka
authors.forename: Naoki
authors.initials: N
authors.lastname: Kusunose
authors.forename: Masahiro
authors.initials: M
authors.lastname: Endo
authors.forename: Hisashi
authors.initials: H
authors.lastname: Suyama
authors.forename: Hiroki
authors.initials: H
authors.lastname: Chikumi
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
authors.forename: Eiji
authors.initials: E
authors.lastname: Shimizu
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D045422:Continuous Positive Airway Pressure; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology* / Q000628:therapy; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012015:Reference Standards; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A