Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes.
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 the 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 we compared the effects of PV IgG and MP on KC. The use of DNA microarray showed that PV IgG down-regulated and MP up-regulated expression of the genes encoding keratinocyte adhesion molecules, antigen-processing proteins, regulators of cell cycle 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 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%, beta-catenin by 37%, gamma-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 the up-regulated synthesis and post-translational modification of the keratinocyte adhesion molecules.
Department of Dermatology, University of California School of Medicine, Davis, CA 95616, USA.
Vu Thuong
VT
Nguyen
Juan
J
Arredondo
Alexander I
AI
Chernyavsky
Yasuo
Y
Kitajima
Mark
M
Pittelkow
Sergei A
SA
Grando
D000818:Animals; D001323:Autoantibodies / Q000494:pharmacology*; D015820:Cadherins / Q000096:biosynthesis; D002448:Cell Adhesion / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D051184:Desmoglein 3; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010392:Pemphigus / Q000188:drug therapy* / Q000276:immunology*; D010766:Phosphorylation; D015534:Trans-Activators / Q000096:biosynthesis; D051176:beta Catenin
D001323:Autoantibodies; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; C071894:DSG3 protein, human; D051184:Desmoglein 3; D007074:Immunoglobulin G; D015534:Trans-Activators; D051176:beta Catenin; D008775:Methylprednisolone