Abstract
Pemphigus is an autoimmune blistering disease targeting the desmosomal proteins desmoglein (Dsg) 1 and Dsg3. Recently, a genetic variant of the Suppression of tumorigenicity 18 (ST18) promoter was reported to cause ST18 up-regulation, associated with pemphigus vulgaris (PV)-IgG-mediated increase in cytokine secretion and more prominent loss of keratinocyte cohesion. Here we tested the effects of PV-IgG and the pathogenic pemphigus mouse anti-Dsg3 antibody AK23 on cytokine secretion and ERK activity in human keratinocytes dependent on ST18 expression. Without ST18 overexpression, both PV-IgG and AK23 induced loss of keratinocyte cohesion which was accompanied by prominent fragmentation of Dsg3 immunostaining along cell borders. In contrast, release of pro-inflammatory cytokines such as IL-1α, IL-6, TNFα, and IFN-γ was not altered significantly in both HaCaT and primary NHEK cells. These experiments indicate that cytokine expression is not strictly required for loss of keratinocyte cohesion. Upon ST18 overexpression, fragmentation of cell monolayers increased significantly in response to autoantibody incubation. Furthermore, production of IL-1α and IL-6 was enhanced in some experiments but not in others whereas release of TNF-α dropped significantly upon PV-IgG application in both EV- and ST18-transfected HaCaT cells. Additionally, in NHEK, application of PV-IgG but not of AK23 significantly increased ERK activity. In contrast, ST18 overexpression in HaCaT cells augmented ERK activation in response to both c-IgG and AK23 but not PV-IgG. Because inhibition of ERK by U0126 abolished PV-IgG- and AK23-induced loss of cell cohesion in ST18-expressing cells, we conclude that autoantibody-induced ERK activation was relevant in this scenario. In summary, similar to the situation in PV patients carrying ST18 polymorphism, overexpression of ST18 enhanced keratinocyte susceptibility to autoantibody-induced loss of cell adhesion, which may be caused in part by enhanced ERK signaling.
Highlights
Pemphigus vulgaris (PV) is a potentially fatal autoimmune disease of the skin and the mucous membranes
The effect of Suppression of tumorigenicity 18 (ST18) overexpression on cytokine release and on the modulation of pemphigus-associated extracellular-signal regulated kinase (ERK) signaling was evaluated since both events would render keratinocytes more susceptible to pemphigus vulgaris (PV)-IgGinduced loss of keratinocyte adhesion
In contrast to control conditions, in which confluent monolayer exposed to PBS or control IgG (c-IgG) obtained from healthy volunteers remained intact, application of both AK23 and PV-IgG (PV-1 and PV-2) for 24 h induced loss of cell adhesion
Summary
Pemphigus vulgaris (PV) is a potentially fatal autoimmune disease of the skin and the mucous membranes. Autoantibodies targeting desmocollin (Dsc) 3, which are rarely present in cases when antibodies against Dsg are missing, were shown to be pathogenic [2,3,4] These desmosomal cadherins are transmembrane proteins forming the adhesive core of desmosomes, a special intercellular junction maintaining the mechanical integrity of tissues and bearing tension primarily if exposed to high levels of mechanical stress such as in the epidermis [5]. With their cytoplasmic tail, via Plakoglobin (PG), and Desmoplakin (DP), the cadherins are linked to the intermediate filament skeleton, another structural unit providing mechanical strength to cells [6, 7]. The effect of ST18 overexpression on cytokine release and on the modulation of pemphigus-associated ERK signaling was evaluated since both events would render keratinocytes more susceptible to PV-IgGinduced loss of keratinocyte adhesion
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