p38MAPK inhibition prevents disease in pemphigus vulgaris mice

Paula Berkowitz, Peiqi Hu, Simon Warren, Zhi Liu, Luis A. Diaz, David S. Rubenstein

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease characterized by detachment of keratinocytes (acantholysis). It has been proposed that PV IgG might trigger signaling and that this process may lead to acantholysis. Indeed, we recently identified a rapid and dose-dependent phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and heat shock protein (HSP) 27 after binding of PV antibodies to cultured keratinocytes. In human keratinocyte cultures, inhibitors of p38MAPK prevented PV IgG-induced phosphorylation of HSP27 and, more importantly, prevented the early cytoskeletal changes associated with loss of cell-cell adhesion. This study was undertaken to (i) determine whether p38MAPK and HSP25, the murine HSP27 homolog, were similarly phosphorylated in an in vivo model of PV and (ii) investigate the potential therapeutic use of p38MAPK inhibition to block blister formation in an animal model of PV. We now report that p38MAPK inhibitors prevented PV blistering disease in vivo. Targeting the end-organ by inhibiting keratinocyte desmosome signaling may be effective for treating desmosome autoimmune blistering disorders.

Original languageEnglish (US)
Pages (from-to)12856-12860
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number34
DOIs
StatePublished - Aug 22 2006
Externally publishedYes

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Pemphigus
p38 Mitogen-Activated Protein Kinases
Keratinocytes
Acantholysis
Desmosomes
Immunoglobulin G
Phosphorylation
HSP27 Heat-Shock Proteins
Therapeutic Uses
Blister
Protein Kinase Inhibitors
Skin Diseases
Cell Adhesion
Animal Models
Antibodies

Keywords

  • Autoimmune
  • Signaling

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

p38MAPK inhibition prevents disease in pemphigus vulgaris mice. / Berkowitz, Paula; Hu, Peiqi; Warren, Simon; Liu, Zhi; Diaz, Luis A.; Rubenstein, David S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 34, 22.08.2006, p. 12856-12860.

Research output: Contribution to journalArticle

Berkowitz, Paula ; Hu, Peiqi ; Warren, Simon ; Liu, Zhi ; Diaz, Luis A. ; Rubenstein, David S. / p38MAPK inhibition prevents disease in pemphigus vulgaris mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 34. pp. 12856-12860.
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