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Papers In Press, published online ahead of print November 4, 2003
Department of Dermatology, University of California at Davis, Sacramento, CA 95817
Corresponding Author: sagrando{at}ucdavis.edu
Pemphigus vulgaris (PV) is a life-threatening autoimmune disease of skin adhesion associated with IgG autoantibodies against keratinocytes (KC). Treatment of PV with systemic corticosteroids is life-saving but the mechanism of the therapeutic action has not been fully understood. We have developed an animal model that demonstrates that methylprednisolone (MP) can block PV IgG induced acantholysis, decreasing the extent of keratinocyte detachment in epidermis of 3-5 day-old nude mice from 77.5 ± 0.6 to 24.1 ± 1.5% (p<0.05). We hypothesized that in addition to immunosuppression, MP may exhibit direct anti-acantholytic effects in epidermis, and compared effects of PV IgG and MP on KC. The use of DNA microarray showed that PV IgG downregulated and MP upregulated expression of the genes encoding the keratinocyte adhesion molecules desmoglein 3 and periplakin, antigen processing proteins, regulators of cell cycle progression and apoptosis, differentiation markers, Na+, K+-ATPase, protein kinases and phosphatases, and serine proteases and their inhibitors. Overall, PV IgG decreased transcription of 198 genes, and increased transcription of 31 genes. MP decreased transcription of 14 genes and increased transcription of 818 genes. Specific effects of PV IgG and MP on keratinocyte adhesion molecules were further investigated by the semi-quantitative western blot and immunofluorescence assays. By immunoblotting, MP increased the protein levels of E-cadherin, and desmogleins 1 and 3 by 300, 180 and 40%, respectively. Specific staining of KC for E-cadherin, and desmogleins 1 and 3 increased by 235, 228 and 148%, respectively. In addition, PV IgG increased the level of phosphorylation of E-cadherin by 42%,
J. Biol. Chem, 10.1074/jbc.M309000200
Submitted on August 14, 2003
Revised on November 4, 2003
Accepted on November 4, 2003
Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes
-catenin by 37%, 
-catenin by 136% and desmoglein 3 by 300%, whereas pretreatment with 0.25 mM MP abolished phosphorylation of these adhesion molecules. These results suggested that therapeutic effects of MP in PV include both upregulated synthesis and postranslational modification of the keratinocyte adhesion molecules targeted by pemphigus autoimmunity.
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