title: Nicotine-Mediated Ca(2+)-Influx Induces IL-8 Secretion in Oral Squamous Cell Carcinoma Cell.
abstract: Cigarette smoking is one of the most important risk factors for the development of various diseases. Nicotine is the most extensively investigated component of cigarette smoke, and a comprehensive analysis of the genes induced by nicotine stimulation revealed that interleukin-8 (IL-8) was induced in oral squamous cell carcinoma cell (OSCC). Based on this background, the signaling mechanisms of nicotine-mediated IL-8 induction in OSCC was investigated. Augmented IL-8 secretion by Ca9-22 cells was blocked by the NF-κB inhibitor L-1-4'-tosylamino-phenylethyl-chloromethyl ketone (TPCK) and the nicotinic acetylcholine receptor (nAChR)-specific inhibitor α-bungarotoxin (αBtx). The downstream signaling pathway was further examined by pre-incubating the cells with inhibitors against mitogen-activated protein kinase (MEK), protein kinase C (PKC), and Ca(2+)/calmodulin-dependent kinase II (CaMK II). Only the CaMK II inhibitor was found to exert an inhibitory effect on nicotine-mediated IL-8 secretion. Pre-treatment of the Ca9-22 cells with the Ca(2+) chelator BAPTA-AM drastically inhibited IL-8 secretion. Although nicotine stimulation induced the phosphorylation of the NF-κB p65 subunit, pre-treatment with BAPTA-AM was found to inhibit this activity significantly. CaMK II-dependent p65 phosphorylation was confirmed by pre-incubation of the cells with CaMK II inhibitor. The results from this study indicate that the binding of nicotine to nAChR induces Ca(2+) influx, which results in the activation and phosphorylation of CaMK II and NF-κB p65, respectively. Nicotine-mediated IL-8 induction should be a trigger for the initiation of various diseases.
authors.affiliation: Division of Applied Oral Sciences, Nihon University Graduate School of Dentistry, Tokyo, Japan.
authors.forename: Kou
authors.initials: K
authors.lastname: Tsunoda
authors.affiliation: Division of Respiratory Medicine, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Tsujino
authors.affiliation: Department of Periodontology, Nihon University School of Dentistry, Tokyo, Japan.|Division of Advanced Dental Treatment, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Koshi
authors.affiliation: Department of Periodontology, Nihon University School of Dentistry, Tokyo, Japan.|Division of Advanced Dental Treatment, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Sugano
authors.affiliation: Department of Periodontology, Nihon University School of Dentistry, Tokyo, Japan.|Division of Advanced Dental Treatment, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Pathology, Nihon University School of Dentistry, Tokyo, Japan.|Division of Immunology and Pathobiology, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Masatake
authors.initials: M
authors.lastname: Asano
mesh_terms: D020121:5' Untranslated Regions; D002038:Bungarotoxins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D019073:HT29 Cells; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D002038:Bungarotoxins; C508606:CXCL8 protein, human; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; C498143:RELA protein, human; D011978:Receptors, Nicotinic; D051996:Transcription Factor RelA; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D014108:Tosylphenylalanyl Chloromethyl Ketone; D004533:Egtazic Acid; D009538:Nicotine; D008156:Luciferases; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium
keywords: CALCIUM; Ca2+/CALMODULIN-DEPENDENT KINASE; INTERLEUKIN-8; NICOTINE