title: CX-659S, a diaminouracil derivative, indirectly inhibits the function of Langerhans cells by blocking the MEK1/2-Erk1/2 pathway in keratinocytes.
abstract: Keratinocytes are an important component of the skin immune system, and keratinocyte-derived cytokines control the function of Langerhans cells. We previously showed that CX-659S, a novel diaminouracil derivative, had an inhibitory effect on hapten-induced contact hypersensitivity reaction in mice. In this study, we investigated the mechanism by which CX-659S elicits its inhibitory effect. CX-659S inhibited the expressions of CD80 and CD86, but not that of CD54, on Langerhans cells in epidermal cell suspensions. Exogenous granulocyte-macrophage colony-stimulating factor restored the CX-659S-induced inhibition of CD80 and CD86 expressions of Langerhans cells. The production of interleukin-2 from allogeneic T cells was also inhibited when the cells were stimulated with CX-659S-treated epidermal cells, and this inhibition was suppressed by the addition of granulocyte-macrophage colony-stimulating factor during CX-659S treatment. As CX-659S significantly inhibited production of granulocyte-macrophage colony-stimulating factor from keratinocytes, CX-659S was thought to indirectly affect Langerhans cells by inhibiting the function of keratinocytes. These effects of CX-659S were preceded by blockade of the phosphorylation of extracellular-signal-regulated kinase 1/2 and their direct activators, mitogen-activated protein kinase/extracellular-signal-regulated kinase 1/2 (MEK1/2), but not p38 mitogen-activated protein kinase or inhibitory nuclear factor kappaBalpha, in keratinocytes. Furthermore, a specific MEK1/2 inhibitor, U0126, mimicked the effect of CX-659S. CX-659S, a keratinocyte-response modifier, would be an effective therapeutic compound to inhibit contact hypersensitivity reaction, its action mechanism being different from those of other immunosuppressive agents such as glucocorticosteroids or cyclosporine A.
authors.affiliation: Department of Dermatology, Kyushu University, Fukuoka, Japan. uchihir@dermatol.med.kyushu-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Koga
authors.forename: Kazunori
authors.initials: K
authors.lastname: Urabe
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Moroi
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
mesh_terms: D000818:Animals; D015703:Antigens, CD; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D002070:Butadienes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D015603:Keratinocytes / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D007801:Langerhans Cells / Q000187:drug effects* / Q000502:physiology*; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000378:metabolism; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D002070:Butadienes; C497965:Cd86 protein, mouse; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D009570:Nitriles; C113580:U 0126; D014498:Uracil; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C418807:CX 659S