Receptor-mediated tobacco toxicity: alterations of the NF-kappaB expression and activity downstream of alpha7 nicotinic receptor in oral keratinocytes.
To gain a mechanistic insight into nicotinic receptor-dependent morbidity of tobacco products in the oral cavity, we studied effects of exposures of normal human oral keratinocytes (KCs) for 24 h to environmental tobacco smoke (ETS) vs. equivalent concentration of pure nicotine. The exposed KCs showed a multifold increase of nuclear factor-kappaB (NF-kappaB) at the mRNA and protein levels, which could be significantly (p<0.05) diminished by alpha-bungarotoxin or transfection with anti-alpha7 small interfering RNA. An increased protein-binding activity of NF-kappaB also could be prevented by blocking alpha7 signaling. The use of pathway inhibitors demonstrated that the Ras/Raf-1/MEK1/ERK steps mediated alpha7-dependent upregulation of NF-kappaB. Thus, exposure of KCs to tobacco may lead to the pathobiologic effects via an intracellular signaling pathway downstream of alpha7 that proceeds through the Ras/Raf-1/MEK1/ERK steps leading to upregulated expression and transactivation of NF-kappaB.
Arredondo
Juan
J
Department of Dermatology, University of California, Davis, USA.
Chernyavsky
Alexander I
AI
Jolkovsky
David L
DL
Pinkerton
Kent E
KE
Grando
Sergei A
SA
D002038:Bungarotoxins / Q000494:pharmacology; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D009061:Mouth Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D012906:Smoke; D014162:Transfection; D064569:alpha7 Nicotinic Acetylcholine Receptor; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D062789:Tobacco Products
D002038:Bungarotoxins; C579167:Chrna7 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; D012906:Smoke; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D018631:ras Proteins