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.