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-α, 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 μ
M
induced secretion of TNF-α, 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-α, 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-α 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 overexpression and the antigen-presenting capacity of monocytes/macrophages, and by upregulation
of IL-1RA.
Key words Monomethylfumarate - Psoriasis - Monocytes - Cytokine formation - IL-10 - TNF-alpha
Received: 16 April 1997