title: P2Y6 receptor signaling pathway mediates inflammatory responses induced by monosodium urate crystals.
abstract: Gout occurs in individuals with hyperuricemia when monosodium urate (MSU) crystals precipitate in tissues and induce acute inflammation via phagocytic cells such as monocytes. MSU crystals have been demonstrated in skin diseases such as tophaceous gout or psoriasis; however, the importance of MSU crystals in the skin is totally unknown. In this study, we found that MSU crystals, through P2Y(6) receptors, stimulated normal human keratinocytes (NHK) to produce IL-1α, IL-8/CXCL8, and IL-6. P2Y(6) receptor expression increased in MSU-stimulated NHK. Both P2Y(6)-specific antagonist and P2Y(6) antisense oligonucleotides significantly inhibited the production of IL-1α, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y(6)-specific antagonist completely inhibited the MSU-induced production of IL-1β by THP-1 cells, a human monocytic cell line. Remarkably, the P2Y(6)-specific antagonist significantly reduced neutrophil influx in both mouse air pouch and peritonitis models. Thus, these results indicate that the P2Y(6) receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout.
authors.affiliation: Department of Dermatology, University of Tokyo, Tokyo, Japan.
authors.forename: Hideya
authors.initials: H
authors.lastname: Uratsuji
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Tada
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kawashima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kamata
authors.forename: Carren Sy
authors.initials: CS
authors.lastname: Hau
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Asano
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugaya
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kadono
authors.forename: Akihiko
authors.initials: A
authors.lastname: Asahina
authors.forename: Shinichi
authors.initials: S
authors.lastname: Sato
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000009:adverse effects* / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006073:Gout / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D033461:Hyperuricemia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011565:Psoriasis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058919:Purinergic P2 Receptor Antagonists / Q000276:immunology* / Q000378:metabolism; D018048:Receptors, Purinergic P2; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D014527:Uric Acid / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D016207:Cytokines; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014527:Uric Acid