Dithranol and dimethylfumarate suppress the interferon-gamma-induced up-regulation of cytokeratin 17 as a putative psoriasis autoantigen in vitro.
In psoriasis an etiopathogenetic vicious circle has been hypothesized in which disease manifestation is triggered by skin-specific autoantigen structures. Autoreactive T cells are supposed to mediate inflammation and hyperproliferation in the epidermopapillary compartment, positively feeding back the expression and accessibility of decisive antigen structures. Recently an epitope within cytokeratin 17 (K17) has been described as such a putative psoriasis autoantigen, which is moreover known to be up-regulated under the influence of proinflammatory interferon-gamma (IFN-gamma), which is abundantly detected in psoriatic plaques. The present study proposes an in vitro model for this presumptive IFN-gamma/K17 autoimmune loop, i.e. the incubation of hyperproliferative human HaCaT keratinocytes with 25 U IFN-gamma/ml for 72 h. This treatment led to a significant up-regulation of K17 protein expression (> or =300%) measured by flow immunocytometry as compared to the untreated control (100%, p < or = 0.05). Preincubation with a subcytotoxic and antiproliferative dithranol concentration as low as 0.3 microM for 2 h prior to the IFN-gamma exposure resulted in a K17 expression that was significantly lower than the IFN-gamma-induced K17 expression reference level. The IFN-gamma-induced K17 expression was also significantly lowered by coincubation with a subcytotoxic and nonantiproliferative concentration of 3 microM dimethylfumarate. The data indicate for dithranol and dimethylfumarate that a part of their antipsoriatic mode of action may be related to a direct down-regulation of putative psoriasis autoantigen structures.
Bonnekoh
B
B
Department of Dermatology and Venereology, Otto von Guericke University, Magdeburg, Germany. bernd.bonnekoh@medizin.uni-magdeburg.de
Böckelmann
R
R
Ambach
A
A
Gollnick
H
H
D000287:Administration, Topical; D000875:Anthralin / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001324:Autoantigens / Q000276:immunology; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000069462:Dimethyl Fumarate; D005434:Flow Cytometry; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007633:Keratins / Q000096:biosynthesis* / Q000276:immunology; D011565:Psoriasis / Q000276:immunology*; D011994:Recombinant Proteins; D015854:Up-Regulation / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D001324:Autoantigens; D005650:Fumarates; D011994:Recombinant Proteins; D007633:Keratins; D007371:Interferon-gamma; D000069462:Dimethyl Fumarate; D000875:Anthralin