MAP kinase abnormalities in hyperproliferative cultured fibroblasts from psoriatic skin.
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.
Dimon-Gadal
S
S
Unité INSERM 427, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
Raynaud
F
F
Evain-Brion
D
D
Keryer
G
G
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000737:chemistry / Q000201:enzymology; D048429:Cell Size / Q000502:physiology; D003470:Culture Media / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011565:Psoriasis / Q000201:enzymology* / Q000473:pathology*; D012867:Skin / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors
D003470:Culture Media; D010982:Platelet-Derived Growth Factor; D015124:8-Bromo Cyclic Adenosine Monophosphate; D017871:Calcium-Calmodulin-Dependent Protein Kinases