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J. Biol. Chem., Vol. 279, Issue 3, 2135-2146, January 16, 2004

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Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes^*

Vu Thuong Nguyen, Juan Arredondo, Alexander I. Chernyavsky, Yasuo Kitajima, Mark Pittelkow¶, and Sergei A. Grando||

From the Department of Dermatology, University of California School of Medicine, Davis, California 95616, the Department of Dermatology, Gifu University, Gifu City 500-8705, Japan, and the ^¶Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905

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%, -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 the up-regulated synthesis and post-translational modification of the keratinocyte adhesion molecules.

Received for publication, August 14, 2003 , and in revised form, November 4, 2003.

^* This work was supported in part by a research grant from the Robert Leet and Clara Guthrie Patterson Trust (to S. A. G.) and the International Pemphigus Research Fund. This work was presented in part at the 62nd and 63rd Annual Meetings of the Society for Investigative Dermatology and published as abstracts (Nguyen, V. T., and Grando, S. A. (2001) J. Investig. Dermatol. 117, 543 (Abstr. 919); Nguyen, V. T., Arredondo, J., Chernyavsky, A., Pittelkow, M. R., Kitajima, Y., and Grando, S. A. (2002) J. Investig. Dermatol. 119, 227 (Abstr. 116). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: 4860 Y St., Ste. 3400, Sacramento, CA 95817. Tel.: 916-734-6057; Fax: 916-734-6793; E-mail: sagrando{at}ucdavis.edu.

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