Receptor-mediated tobacco toxicity:: Alterations of the NF-κB expression and activity downstream of α7 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-kappa B (NF-kappa B) at the mRNA and protein levels, which could be significantly (p<0.05) diminished by a-bungarotoxin or transfection with anti-alpha 7 small interfering RNA. An increased protein-binding activity of NF-kappa B also could be prevented by blocking alpha 7 signaling. The use of pathway inhibitors demonstrated that the Ras/Raf-1/MEK1/ERK steps mediated alpha 7-dependent upregulation of NF-kappa B. Thus, exposure of KCs to tobacco may lead to the pathobiologic effects via an intracellular signaling pathway downstream of 0 that proceeds through the Ras/Raf-1/N4EK1/ERK steps leading to upregulated expression and transactivation of NF-kappa B. (c) 2007 Elsevier Inc. All rights reserved.