Hypoxia, but not reoxygenation, induces interleukin 6 gene expression through NF-kappa B activation.
Interleukin (IL) 6 is one of major mediators of inflammation, and IL-6 gene activation during hypoxia/reoxygenation has been implicated in the pathogenesis of ischemia/reperfusion injury. However, molecular events involved in IL-6 gene expression during hypoxia/reoxygenation remain to be identified. We have previously shown that NF-kappa B plays an essential and indispensable role in the transcriptional activation of the IL-6 gene induced by various stimuli, including IL-1 and tumor necrosis factor-alpha. We show here that hypoxia, but not reoxygenation, induces the activation of NF-kappa B through the degradation of a major inhibitor of NF-kappa B, I kappa B alpha. This hypoxia-induced NF-kappa B activation resulted in the kappa B-dependent transcriptional activation of the IL-6 gene. Interestingly, the time course of hypoxia-induced NF-kappa B activation was rather slow as compared with those of NF-kappa B activation induced by other stimuli, such as IL-1: a significant NF-kappa B activation was not observed before 1 hr of hypoxia treatment and persisted for up to 7 hr of hypoxia treatment. However, hypoxia-induced NF-kappa B activation was not inhibited by cycloheximide, which indicates that hypoxia directly triggers NF-kappa B activation. Furthermore, while hypoxia is unlikely to generate reactive oxygen intermediates, pretreatment of cells with antioxidants such as N-acetyl cysteine and alpha-tocopherol inhibited NF-kappa B activation induced by hypoxia. Thus, we discuss possible implications of these results for a postulated role of reactive oxygen intermediates in NF-kappa B activation.
Muraoka
K
K
Department of Molecular Pathology, School of Medicine, Kanazawa University, Ishikawa, Japan.
Shimizu
K
K
Sun
X
X
Zhang
Y K
YK
Tani
T
T
Hashimoto
T
T
Yagi
M
M
Miyazaki
I
I
Yamamoto
K
K
D000818:Animals; D005786:Gene Expression Regulation / Q000276:immunology*; D000860:Hypoxia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics*; D007739:L Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000502:physiology; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000276:immunology*; D015533:Transcriptional Activation
D015850:Interleukin-6; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D010100:Oxygen