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Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes
Xuming Mao, … , Eric M. Mukherjee, Aimee S. Payne
Xuming Mao, … , Eric M. Mukherjee, Aimee S. Payne
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e92253. https://doi.org/10.1172/jci.insight.92253.
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Research Article Dermatology

Stat3 regulates desmoglein 3 transcription in epithelial keratinocytes

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Abstract

Pemphigus vulgaris (PV) is an epithelial blistering disease caused by autoantibodies to the desmosomal cadherin desmoglein 3 (DSG3). Glucocorticoids improve disease within days by increasing DSG3 gene transcription, although the mechanism for this observation remains unknown. Here, we show that DSG3 transcription in keratinocytes is regulated by Stat3. Treatment of primary human keratinocytes (PHKs) with hydrocortisone or rapamycin, but not the p38 MAPK inhibitor SB202190, significantly increases DSG3 mRNA and protein expression and correspondingly reduces phospho-S727 Stat3. Stat3 inhibition or shRNA-knockdown also significantly increases DSG3 mRNA and protein levels. Hydrocortisone- or rapamycin-treated PHKs demonstrate increased number and length of desmosomes by electron microscopy and are resistant to PV IgG–induced loss of cell adhesion, whereas constitutive activation of Stat3 in PHKs abrogates DSG3 upregulation and inhibits hydrocortisone and rapamycin’s therapeutic effects. Topical hydrocortisone, rapamycin, or Stat3 inhibitor XVIII prevents autoantibody-induced blistering in the PV passive transfer mouse model, correlating with increased epidermal DSG3 expression and decreased phospho-S727 Stat3. Our data indicate that glucocorticoids and rapamycin upregulate DSG3 transcription through inhibition of Stat3. These studies explain how glucocorticoids rapidly improve pemphigus and may also offer novel insights into the physiologic and pathophysiologic regulation of desmosomal cadherin expression in normal epidermis and epithelial carcinomas.

Authors

Xuming Mao, Michael Jeffrey T. Cho, Christoph T. Ellebrecht, Eric M. Mukherjee, Aimee S. Payne

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Figure 6

Stat3 inhibition prevents skin blistering in a pemphigus vulgaris (PV) mouse model.

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Stat3 inhibition prevents skin blistering in a pemphigus vulgaris (PV) m...
(A) Topical Stat3 inhibition results in increased desmoglein 3 (DSG3) protein levels and decreased phospho-S727 Stat3 (pStat3) in mouse epidermis. Results are representative of 2 different experiments. Stat3 inhibitor XVIII abrogates skin blisters induced by passive transfer of PV IgG at the gross (B) and histologic levels (C, left panels), despite equivalent binding of PV IgG to the keratinocyte cell surface (C, right panels). Scale bars: 100 μm. Results are representative of 2 different experiments. (D) A significant decrease in skin blister scores is observed in PV model mice treated with topical Stat3 inhibitors. *P < 0.05 (Kruskal–Wallis test).

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