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(American Journal of Pathology. 2005;166:597-613.)
© 2005 American Society for Investigative Pathology

Receptor-Mediated Tobacco Toxicity

Regulation of Gene Expression through {alpha}3ß2 Nicotinic Receptor in Oral Epithelial Cells

Juan Arredondo*, Alexander I. Chernyavsky*, Lisa M. Marubio{dagger}, Arthur L. Beaudet{dagger}, David L. Jolkovsky{ddagger}, Kent E. Pinkerton§ and Sergei A. Grando*

From the Department of Dermatology,* University of California at Davis, School of Medicine, Davis, California; the Center for Health and the Environment,§ University of California, Davis, California; the Section of Periodontics,{ddagger} School of Dentistry, University of California, Los Angeles, California; and the Department of Molecular and Human Genetics,{dagger} Baylor College of Medicine, Houston, Texas

Tobacco is a known cause of oral disease but the mechanism remains elusive. Nicotine (Nic) is a likely culprit of pathobiological effects because it displaces the local cytotransmitter acetylcholine from the nicotinic receptors (nAChRs) expressed by oral keratinocytes (KCs). To gain a mechanistic insight into tobacco-induced morbidity in the oral cavity, we studied effects of exposures to environmental tobacco smoke (ETS) versus equivalent concentration of pure Nic on human and murine KCs. Both ETS and Nic up-regulated expression of cell cycle and apoptosis regulators, differentiation marker filaggrin, and signal transduction factors at both the mRNA and protein levels. These changes could be abolished in cultured human oral KCs transfected with anti-{alpha}3 small interfering RNA or treated with the {alpha}3ß2-preferring antagonist {alpha}-conotoxin MII. Functional inactivation of {alpha}3-mediated signaling in {alpha}3–/– mutant KCs prevented most of the ETS/Nic-dependent changes in gene expression. To determine relevance of the in vitro findings to the in vivo situation, we studied gene expression in oral mucosa of neonatal {alpha}3+/+ and {alpha}3–/– littermates delivered by heterozygous mice soon after their exposures to ETS or equivalent concentration of pure Nic in drinking water. In addition to reverse transcriptase-polymerase chain reaction and Western blot, the ETS/Nic-dependent alterations in gene expression were also detected by semiquantitative immunofluorescence assay directly in KCs comprising murine oral mucosa. Only wild-type mice consistently developed significant (P < 0.05) changes in the gene expression. These results identified {alpha}3ß2 nAChR as a major receptor mediating effects of tobacco products on KC gene expression. Real-time polymerase chain reaction demonstrated that in all three model systems the common genes targeted by {alpha}3ß2-mediated ETS/Nic toxicity were p21, Bcl-2, NF-{kappa}B, and STAT-1. The expression of the nAChR subunits {alpha}5 and ß2 and the muscarinic receptor subtypes M2 and M3 was also altered. This novel mechanism offers innovative solutions to ameliorate the tobacco-related cell damage and intercede in disease pathways, and may shed light on general mechanisms regulating and driving tobacco-related morbidity in human cells.




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