title: Sustained exposure to cytokines and hypoxia enhances excitability of oxygen-sensitive type I cells in rat carotid body: correlation with the expression of HIF-1α protein and adrenomedullin.
abstract: Recent studies in our laboratory demonstrated that chronic hypoxia (CH) induces a localized inflammatory response in rat carotid body that is characterized by macrophage invasion and increased expression of inflammatory cytokines. Moreover, CH-induced increased hypoxic sensitivity is blocked by concurrent treatment with the common anti-inflammatory drugs, ibuprofen and dexamethasone. The present study examines the hypothesis that selected cytokines enhance the excitability of oxygen-sensitive type I cells in the carotid body, and that downstream effects of cytokines involve upregulation of the transcription factor, hypoxia inducible factor-1α (HIF-1α). Cultured type I cells were exposed for 24 h to hypoxia and/or a cocktail of cytokines consisting of interleukin-1β, interleukin-6, and tumor necrosis factor-α. Subsequent evaluation of hypoxia-evoked intracellular Ca(2+)-responses showed that previous exposure to cytokines plus hypoxia resulted in a 110% (p<0.001) increase in cell excitability, whereas exposure to cytokines or hypoxia alone elicited smaller increases of 22% (not significant) and 35% (p<0.01), respectively. These changes were correlated with increased immunostaining for HIF-1α in similarly treated type I cells, where exposure to cytokines plus hypoxia promoted the nuclear translocation of the transcription factor. Moreover, treatment with cytokines and/or hypoxia elevated the expression of the HIF-1-regulated gene, adrenomedullin. These in vitro results are supported by studies which show that elevated type I cell sensitivity following in vivo CH is blocked by concurrent treatment with ibuprofen. The data suggest that CH-induced adaptation in arterial chemoreceptors may in part be mediated by cytokine/hypoxia-induced upregulation of HIF-1α, and consequent enhanced expression of specific hypoxia-sensitive genes in type I cells.
authors.affiliation: Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah 84108, USA.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Liu
authors.forename: Liang
authors.initials: L
authors.lastname: He
authors.forename: Bruce
authors.initials: B
authors.lastname: Dinger
authors.forename: Larry
authors.initials: L
authors.lastname: Stensaas
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fidone
mesh_terms: D053607:Adrenomedullin / Q000235:genetics*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002344:Carotid Body / Q000166:cytology / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008564:Membrane Potentials; D051381:Rats; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D053607:Adrenomedullin; D002118:Calcium
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