The antipsoriatic dimethyl-fumarate suppresses interferon-gamma -induced ICAM-1 and HLA-DR expression on hyperproliferative keratinocytes. Quantification by a culture plate-directed APAAP-ELISA technique.
The derivatives of fumaric acid show antipsoriatic effects but details of the mechanism of action are largely unknown. The study focused on the effect of fumaric acid, dimethyl-fumarate, Zn-, Ca- and Mg-monoethyl-fumarate on the interferon-gamma (IFN-gamma)-induced expression of ICAM-1 and HLA-DR molecules on keratinocytes. Human hyperproliferative keratinocytes of the HaCaT cell line were exposed to IFN-gamma (10 U/ml) alone or in combination with fumaric acid and its derivatives for 48 hrs. The effect of fumarates was investigated semiquantitatively using the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method. Subsequently, the effect of dimethyl-fumarate, the main component of "fumaric acid therapy", was evaluated quantitatively by means of an APAAP-ELISA technique. The semiquantitative evaluation revealed that in the micromolar dose range investigated only dimethyl-fumarate demonstrated substantial growth inhibition and down-regulation of the cell surface markers. In the quantitative evaluation, dimethyl-fumarate significantly (p</=0.05) suppressed the expression of ICAM-1 (84%) and HLA-DR (67%) on HaCaT keratinocytes at a subtoxic concentration of 4.0 microM as compared to untreated controls (100%). In contrast, concentrations of 4.0, 12 and 35 microM dimethyl-fumarate had no influence on the ICAM-1 and HLA-DR expression on IFN-gamma-exposed normal human epidermal keratinocytes in primary cultures. Thus, there is experimental evidence that dimethyl-fumarate may exert its antipsoriatic effect not only as an antiproliferative agent but also by down-regulation of ICAM-1 and HLA-DR molecules on hyperproliferative keratinocytes.
Sebok
B
B
Department of Dermatology, University of Cologne, Cologne, Germany.
Bonnekoh
B
B
Vetter
R
R
Schneider
I
I
Gollnick
H
H
Mahrle
G
G
D002455:Cell Division; D002478:Cells, Cultured; D003879:Dermatologic Agents / Q000494:pharmacology*; D000069462:Dimethyl Fumarate; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005650:Fumarates / Q000494:pharmacology*; D006684:HLA-DR Antigens / Q000032:analysis / Q000187:drug effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000187:drug effects*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015603:Keratinocytes / Q000737:chemistry / Q000187:drug effects*; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology; D012016:Reference Values; D012680:Sensitivity and Specificity
D003879:Dermatologic Agents; D005650:Fumarates; D006684:HLA-DR Antigens; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D000069462:Dimethyl Fumarate