title: Epithelial TRPV1 signaling accelerates gingival epithelial cell proliferation.
abstract: Transient receptor potential cation channel subfamily V member 1 (TRPV1), a member of the calcium-permeable thermosensitive transient receptor potential superfamily, is a sensor of thermal and chemical stimuli. TRPV1 is activated by noxious heat (> 43°C), acidic conditions (pH < 6.6), capsaicin, and endovanilloids. This pain receptor was discovered on nociceptive fibers in the peripheral nervous system. TRPV1 was recently found to be expressed by non-neuronal cells, such as epithelial cells. The oral gingival epithelium is exposed to multiple noxious stimuli, including heat and acids derived from endogenous and exogenous substances; however, whether gingival epithelial cells (GECs) express TRPV1 is unknown. We show that both TRPV1 mRNA and protein are expressed by GECs. Capsaicin, a TRPV1 agonist, elevated intracellular Ca(2+) levels in the gingival epithelial cell line, epi 4. Moreover, TRPV1 activation in epi 4 cells accelerated proliferation. These responses to capsaicin were inhibited by a specific TRPV1 antagonist, SB-366791. We also observed GEC proliferation in capsaicin-treated mice in vivo. No effects were observed on GEC apoptosis by epithelial TRPV1 signaling. To examine the molecular mechanisms underlying this proliferative effect, we performed complementary (c)DNA microarray analysis of capsaicin-stimulated epi 4 cells. Compared with control conditions, 227 genes were up-regulated and 232 genes were down-regulated following capsaicin stimulation. Several proliferation-related genes were validated by independent experiments. Among them, fibroblast growth factor-17 and neuregulin 2 were significantly up-regulated in capsaicin-treated epi 4 cells. Our results suggest that functional TRPV1 is expressed by GECs and contributes to the regulation of cell proliferation.
authors.affiliation: Laboratory of Periodontology and Immunology, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Division of Periodontology, Department of Oral Biological Science, Niigata University Faculty of Dentistry, Niigata, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Laboratory of Periodontology and Immunology, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Division of Periodontology, Department of Oral Biological Science, Niigata University Faculty of Dentistry, Niigata, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Laboratory of Periodontology and Immunology, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan Division of Periodontology, Department of Oral Biological Science, Niigata University Faculty of Dentistry, Niigata, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Division of Periodontology, Department of Oral Biological Science, Niigata University Faculty of Dentistry, Niigata, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tabeta
authors.affiliation: General Dentistry and Clinical Education Unit, Niigata University Medical and Dental Hospital, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Laboratory of Periodontology and Immunology, Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan kaz@dent.niigata-u.ac.jp.
authors.forename: K
authors.initials: K
authors.lastname: Yamazaki
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000032:analysis; D020869:Gene Expression Profiling; D005881:Gingiva / Q000166:cytology* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000032:analysis; D009619:Nociceptors / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D018689:Sensory System Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000813:Anilides; D002934:Cinnamates; C484724:FGF17 protein, human; C484726:Fgf17 protein, mouse; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; C106766:NRG2 protein, human; D009414:Nerve Growth Factors; C491453:Nrg2 protein, mouse; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; D005346:Fibroblast Growth Factors; D002211:Capsaicin
keywords: capsaicin; epithelium; gingiva; microarray analysis; periodontal diseases; transient receptor potential cation channels