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 κBα, 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.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology