MAP Kinase Abnormalities in Hyperproliferative Cultured Fibroblasts from Psoriatic Skin

Abstract

Several studies indicate that dermal fibroblasts have a specific role in the pathophysiology of psoriasis. We have previously found that cultured fibroblasts from psoriatic patients are hyperproliferative and have low cyclic AMP-dependent protein kinase activity. In this study, we observed that these cells are also larger than normal. Given the key role of mitogen-activated protein kinases (MAPK) in the regulation of cell proliferation and cytoskeleton function, we characterized MAPK in psoriatic fibroblasts and in normal fibroblasts. Serum and platelet-derived growth factor treatment of serum-deprived fibroblasts led to a larger increase in MAPK activity in psoriatic cells than in normal cells. We then purified MAPK by ion-exchange chromatography. MAPK activity was again found to be significantly higher in psoriatic fibroblasts than in normal cells, both when deprived of serum (p < 0.01) and when stimulated with serum (p < 0.05). Interestingly, 8-bromo-cAMP treatment inhibited serum-stimulated MAPK phosphorylation in normal fibroblasts but had no effect in psoriatic fibroblasts. We observed a temporal variation in nuclear localization of phosphorylated MAPK in cultured fibroblasts stimulated by either serum or platelet-derived growth factor. No difference in the localization of phosphorylated MAPK in normal and psoriatic skins was found. Psoriatic fibroblasts are the first example of a MAPK pathway abnormality in large human benign hyperproliferative cells.