Response of keratinocytes from normal and psoriatic epidermis to interferon-gamma differs in the expression of zinc-alpha(2)-glycoprotein and cathepsin D

Psoriasis is a T cell-mediated inflammatory disease characterized by hyperp roliferation and by aberrant differentiation. We found cathepsin D and zinc -alpha(2)-glycoprotein, two catalytic enzymes associated with apoptosis and desquamation, to be present in the stratum corneum of the normal epidermis but absent from the psoriatic plaque. Psoriasis is characterized by an alt ered response to interferon-gamma (IFN-gamma), including the induction of a poptosis in normal but not in psoriatic keratinocytes, often with opposite effects on gene expression of suprabasal proteins. We found that IFN-gamma binding and signaling were attenuated in psoriasis: The IFN-gamma receptor, the signal transducer and activator of transcription STAT-1, and the inter feron regulatory factor IRF-1 were strongly up-regulated by IFN-gamma in no rmal keratinocytes, but not in psoriatic ones. IFN-gamma strongly up-regula ted the expression of the catalytic enzymes cathepsin D and zinc-alpha(2)-g lycoprotein in normal keratinocytes but down-regulated them in psoriatic on es; the reverse was true of the apoptotic suppressor bcl-2. We believe that the aberrant response to IFN-gamma plays a central role in the pathophysio logy of psoriasis, particularly the disruption of apoptosis and desquamatio n.