A critical role for p38 map kinase in NF-kappaB signaling during intermittent hypoxia/reoxygenation.
NF-kappaB-dependent inflammatory gene expression is induced by intermittent hypoxia/reoxygenation (IHR), an event that we have hypothesized may contribute to the cardiovascular pathophysiology associated with obstructive sleep apnoea syndrome (OSAS). Here, we have investigated the cellular signaling mechanisms involved. Using an established endothelial cell in vitro model, we confirm a selective activation of the pro-inflammatory transcription factor NF-kappaB over the adaptive hypoxia-inducible factor-1 (HIF-1) in IHR-stimulated bovine aortic endothelial cells. IHR activates the I-kappaB kinase (IKK) complex, leading to phosphorylation/degradation of I-kappaB alpha. IHR activates p38 MAPK and pharmacological inhibition of p38 (using SB 203580, 10 microM) abolishes NF-kappaB activation by IHR. Furthermore, depletion of p38 using siRNA significantly reduces IHR-induced NF-kappaB activity. Thus, IHR activates NF-kappaB in an IKK-dependent manner signaled at least in part via activation of p38 MAPK.
Ryan
Silke
S
School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
McNicholas
Walter T
WT
Taylor
Cormac T
CT
D000332:Aerobiosis; D000693:Anaerobiosis; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000201:enzymology*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D051793:Hypoxia-Inducible Factor 1; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D010100:Oxygen