Although the effectiveness of systemic antipsoriatic treatment with
fumaric acid esters has been proven, their mode of action is still not understood. 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 investigated the effect of
monomethylfumarate (MMF) on proinflammatory (TNF-alpha, IL-12) and antiinflammatory (IL-10, IL-1RA)
cytokine production by peripheral blood mononuclear cells (PBMC) and separated monocytes. In 24-h PBMC cultures from both psoriatic patients (n = 6-13) and healthy volunteers (n = 7-9), MMF at 100 microM induced secretion of
TNF-alpha,
IL-10, and
IL-1RA. Kinetics of
IL-10 protein and
mRNA expression indicated de novo production. Moreover, MMF significantly augmented
endotoxin-induced synthesis of
TNF-alpha,
IL-10 and
IL-1RA. In contrast, no influence on
IL-12 secretion was found. Similar effects of MMF in purified monocytes indicated these cells to be responsible for aberrant
cytokine formation. Furthermore, enhanced expression of costimulatory molecules after MMF stimulation confirmed monocyte activation. Multiple restimulation with
fumaric acid esters in vitro, however, and immunomonitoring in a patient during
Fumaderm initial
therapy suggested that initial monocyte activation is followed by subsequent deactivation associated with an antiinflammatory response. Our results may explain 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 have antipsoriatic activity by diminishing type-1/proinflammatory
cytokine over-expression and the
antigen-presenting capacity of monocytes/macrophages, and by upregulation of
IL-1RA.