THE ANTIPSORIATIC AGENT DIMETHYLFUMARATE IMMUNOMODULATES T-CELL CYTOKINE SECRETION AND INHIBITS CYTOKINES OF THE PSORIATIC CYTOKINE NETWORK

Interactions between infiltrating T cells and keratinocytes via the se cretion of the TH1 cytokines interleukin (IL) 2 and interferon gamma ( INF-gamma), the keratinocyte growth factor transforming growth factor alpha (TGF-alpha) and the cytokines IL-6, and IL-8 are thought to be t he predominant mechanisms inducing skin lesions in psoriatic patients. Systemic treatment of psoriasis with fumaric acid derivatives (FAEs) has been reported to be effective in the treatment of psoriasis, but t he mode of action is still unknown.. To clarify this phenomenon, kerat inocytes from psoriatic patients as well as from healthy volunteers we re mono- and cocultured with HUT 78 T cells with/without the addition of FAEs; the cytokine concentrations were then measured in the culture supernatants, Furthermore, mRNA expression was determined in epiderma l growth factor (EGF) -activated keratinocytes as well as in phytohaem agglutinin (PHA)-activated HUT 78 T cells. Only dimethylfumarate (DMF) diminished IL-6 and TCF-alpha secretion in the psoriatic cocultures. However, it did not have this effect on cocultures from control subjec ts or on monocultures. DMF suppresses EGF-induced TGF-alpha mRNA induc tion in psoriatic keratinocytes. DMF inhibited INF-gamma secretion in all cultures but stimulated the IL-10 secretion. This immunomodulation away from the TH1 cytokine IFN-gamma to the TH2 cytokine IL-10 was co nfirmed in HUT 78 T cells by Northern blot analysis. An increased numb er of eosinophils is a known side-effect in patients treated with this drug, suggesting a clinical relevance of this immunomodulation ill vi vo. This immunomodulation and the suppression of cytokines from the ps oriatic cytokine network could be responsible for the beneficial effec t of DMF in the treatment of a hyperproliferative and TH1 cytokine-med iated skin disease.