title: Role of the aryl hydrocarbon receptor in tobacco smoke extract-induced matrix metalloproteinase-1 expression.
abstract: Findings from large epidemiologic studies indicate that there is a link between smoking and extrinsic skin ageing. We previously reported that matrix metalloproteinases (MMPs) mediate connective tissue damage in skin exposed to tobacco smoke extracts. Tobacco smoke contains more than 3800 constituents, including numerous water-insoluble polycyclic aromatic hydrocarbons (PAHs) that trigger aryl hydrocarbon receptor (AhR) signalling pathways. To analyse the molecular mechanisms involved in tobacco smoke-induced skin ageing, we exposed primary human fibroblasts and keratinocytes to tobacco smoke extracts. Hexane- and water-soluble tobacco smoke extracts significantly induced MMP-1 mRNA in both human cultured fibroblasts and keratinocytes in a dose-dependent manner. To clarify the involvement of the AhR pathway, we used a stable AhR-knockdown HaCaT cell line. AhR knockdown abolished the increased transcription of the AhR-dependent genes CYP1A1/CYP1B1 and MMP-1 induced by either of the tobacco smoke extracts. Furthermore, the tobacco smoke extracts induced 7-ethoxyresorufin-O-deethylase activity, which was almost completely abolished by AhR knockdown. Likewise, treating fibroblasts with AhR pathway inhibitors, that is, the flavonoids 3-methoxy-4-nitroflavone and α-naphthoflavone, blocked the expression of CYP1B1 and MMP-1. These findings suggest that the tobacco smoke extracts induce MMP-1 expression in human fibroblasts and keratinocytes via activation of the AhR pathway. Thus, the AhR pathway may be pathogenetically involved in extrinsic skin ageing.
authors.affiliation: Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ono
authors.forename: Kan
authors.initials: K
authors.lastname: Torii
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Shintani
authors.forename: Emi
authors.initials: E
authors.lastname: Nishida
authors.forename: Motoki
authors.initials: M
authors.lastname: Nakamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shirakata
authors.forename: Thomas
authors.initials: T
authors.lastname: Haarmann-Stemmann
authors.forename: Josef
authors.initials: J
authors.lastname: Abel
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.forename: Akimichi
authors.initials: A
authors.lastname: Morita
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006586:Hexanes / Q000494:pharmacology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015595:Skin Aging / Q000187:drug effects / Q000502:physiology*; D012995:Solubility; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D006586:Hexanes; D018336:Receptors, Aryl Hydrocarbon; D014028:Tobacco Smoke Pollution; D001189:Aryl Hydrocarbon Hydroxylases; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1