Response of keratinocytes from normal and psoriatic epidermis to interferon‐γ differs in the expression of zinc‐α₂‐glycoprotein and cathepsin D

Abstract

Psoriasis is a T cell-mediated inflammatory disease characterized by hyperproliferation 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 altered response to interferon-gamma (IFN-gamma), including the induction of apoptosis 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 interferon regulatory factor IRF-1 were strongly up-regulated by IFN-gamma in normal keratinocytes, but not in psoriatic ones. IFN-gamma strongly up-regulated the expression of the catalytic enzymes cathepsin D and zinc-alpha(2)-glycoprotein in normal keratinocytes but down-regulated them in psoriatic ones; 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 pathophysiology of psoriasis, particularly the disruption of apoptosis and desquamation.

CD56brightCD16– NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation

“…Cross-talk between IFN-c-releasing lymphocytes and keratinocytes is critical for psoriasis development and persistence. Although IFN-c has antiproliferative activity on normal keratinocytes, it failed to block cell cycling in psoriatic keratinocytes and decreased STAT-1 and IRF-1, which are both involved in the regulation of keratinocyte responsiveness to IFN-c [4,5].…”

“…Epidermal changes, consisting of keratinocyte hyperproliferation and altered differentiation, are believed to depend on genetically determined dysregulation of gene expression pathways involved in keratinocyte responsiveness to leukocyte-derived proinflammatory signals [4][5][6]. The role of the immune system in the pathogenesis of the disease has been widely documented [7,8].…”

Cathepsin D—Many functions of one aspartic protease

“…2.1.3 CD role in skin development and function-In addition to the role of CD in brain and retina, altered expression of CD in the skin has been reported during wound healing and psoriasis, a hyperproliferative skin disorder [54,97,98]. CD protein expression and enzymatic activity increases during epidermal differentiation.…”

Procathepsin D secreted by HaCaT keratinocyte cells – A novel regulator of keratinocyte growth

“…In skin, increased levels of the mature form of CD have been shown in squamous cell carcinoma (Maurizi et al, 1996;Kawada et al, 1997) and also in basal keratinocytes during hyperproliferative skin disorders such as psoriasis (Chen et al, 2000). The involvement of different isoforms of CD in epidermal cell differentiation was also suggested.…”