title: Synergistic augmentation of ATP-induced interleukin-6 production by arsenite in HaCaT cells.
abstract: Chronic arsenic exposure causes cutaneous diseases such as hyperkeratosis and skin cancer. However, little information has been available regarding the molecular mechanisms underlying these symptoms. Because extracellular ATP and interleukin-6 (IL-6) are involved in pathological aspects of cutaneous diseases, we examined whether sodium arsenite (As(III)) affects ATP-induced IL-6 production in human epidermal keratinocyte HaCaT cells. The results showed that the addition of As(III) into the medium of HaCaT cells dose dependently increased the production of IL-6 induced by extracellular ATP, although As(III) alone had no effect on IL-6 production. To elucidate the mechanism of the synergistic effect of As(III) on IL-6 production by extracellular ATP, we next examined the phosphorylation of p38, ERK and epidermal growth factor receptor (EGFR), since we found that these signaling molecules were stimulated by exposure to extracellular ATP. The results indicated that ATP-induced phosphorylation of p38, ERK and EGFR was synergistically enhanced by co-exposure to As(III). To clarify the mechanisms underlying the enhanced phosphorylation of p38, ERK and EGFR by As(III), we explored two possible mechanisms: the inhibition of extracellular ATP degradation and the inhibition of protein tyrosine phosphatases (PTPs) activity by As(III). The degradation of extracellular ATP was not changed by As(III), whereas the activity of PTPs was significantly inhibited by As(III). Our results suggest that As(III) augments ATP-induced IL-6 production in HaCaT cells through enhanced phosphorylation of the EGFR and p38/ERK pathways, which is associated with the inhibition of PTPs activity.
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Sumi
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Asao
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan.
authors.forename: Hideta
authors.initials: H
authors.lastname: Okada
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Yogi
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Miyataka
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima, 770-8514, Japan. himenos@ph.bunri-u.ac.jp.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Himeno
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology; D015603:Keratinocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation; D017670:Sodium Compounds / Q000633:toxicity*
chemical_list: D018053:Arsenites; C508600:IL6 protein, human; D015850:Interleukin-6; D017670:Sodium Compounds; C017947:sodium arsenite; D000255:Adenosine Triphosphate; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: ATP; Arsenic; EGFR; IL-6; Protein tyrosine phosphatases