Redox-dependent regulation of interleukin-8 by tumor necrosis factor-alpha in lung epithelial cells.
Increasing evidence supports a major role for interleukin-8 (IL-8), a potent neutrophil chemoattractant, in the chronic progression of inflammatory lung diseases. The present studies were designed to characterize the molecular events involved in IL-8 induction in pulmonary epithelial cells in response to tumor necrosis factor-alpha (TNF-alpha). IL-8 induction by TNF-alpha was redox sensitive, as indicated by electron spin resonance analysis and inhibition with membrane permeable hydroxyl scavengers. Furthermore using cell transfection and mobility shift assays, it was found that transcriptional activation of the IL-8 gene required TNF-alpha-induced activation and binding of nuclear factor-kappaB (NF-kappaB)- and NF-IL-6, nuclear transcription factors to regulatory elements in the IL-8 promoter. Activation of the IL-8 promoter by these transcription factors was also redox-sensitive. This response was mediated through the TNF-R1 receptor (p55), and not the TNF-R2 (p75) receptor, although both receptors can be found on pulmonary epithelial cells. Taken together these studies indicate that TNF-alpha-induced redox changes in lung epithelial cells are responsible for the transcriptional activation of IL-8 and that coordinate activation of NF-kappaB and NF-IL-6 mediate the response.
Simeonova
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PP
Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA. phs9@cdc.gov
Leonard
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Flood
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Shi
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Luster
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MI
D015703:Antigens, CD / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha