INFLUENCE OF MONOMETHYLFUMARATE ON MONOCYTIC CYTOKINE FORMATION - EXPLANATION FOR ADVERSE AND THERAPEUTIC EFFECTS IN PSORIASIS

Although the effectiveness of systemic antipsoriatic treatment with fu maric acid esters has been proven, their mode of action is still not u nderstood, Recent results indicate their potency in inducing cytokine production in stimulated T cells, Since monocytes and their cytokines are also considered to be of pathogenic importance in psoriasis, we in vestigated the effect of monomethylfumarate (MMF) on proinflammatory ( TNF-alpha, IL-12) and antiinflammatory (IL-10, IL-1RA) cytokine produc tion by peripheral blood mononuclear cells (PBMC) and separated monocy tes, In 24-h PBMC cultures from both psoriatic patients (n = 6-13) and healthy volunteers (n = 7-9), MMF at 100 mu M induced secretion of TN F-alpha, IL-10, and IL-1RA, Kinetics of IL-10 protein and mRNA express ion indicated de novo production, Moreover, MMF significantly augmente d endotoxin-induced synthesis of TNF-alpha, IL-10 and IL-IRA, In contr ast, no influence on IL-12 secretion was found, Similar effects of MMF in purified monocytes indicated these cells to be responsible for abe rrant cytokine formation, Furthermore, enhanced expression of costimul atory molecules after MMF stimulation confirmed monocyte activation, M ultiple restimulation with fumaric acid esters in vitro, however, and immunomonitoring in a patient during Fumaderm initial therapy suggeste d that initial monocyte activation is followed by subsequent deactivat ion associated with an antiinflammatory response, Our results may expl ain the well-known effects of therapy with fumaric acid esters, Thus, initial treatment is often accompanied by adverse effects which may be caused by MMF-induced TNF-alpha formation, The change in the IL-10/IL -12 balance as a result of elective induction of IL-10, however, may h ave antipsoriatic activity by diminishing type-1/proinflammatory cytok ine overexpression and the antigen-presenting capacity of monocytes/ma crophages, and by upregulation of IL-1RA.