Neural nitric oxide synthase participates in pemphigus vulgaris acantholysis through upregulation of Rous sarcoma, mammalian target of rapamycin and focal adhesion kinase.
Pemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis produced as a consequence of desmoglein (Dsg) and non-Dsg autoantibodies binding to several targeting molecules localized on the membrane of keratinocytes. Nitric oxide (NO) may exert a pathogenic function in several immunological processes. We have previously demonstrated that neural nitric oxide synthase (nNOS) plays part in PV acantholysis. Also, our group has described a relevant role for HER [human epidermal growth factor receptor (EGFR) related] isoforms and several kinases such as Src (Rous sarcoma), mammalian target of rapamycin (mTOR) and focal adhesion kinase (FAK), as well as caspases in PV development. Using a passive transfer mouse model of PV, we aimed to investigate the relationship between the increase in nNOS and EGFR, Src, mTOR and FAK kinase upregulation observed in PV lesions. Our results revealed a new function for nNOS, which contributes to EGFR-mediated PV acantholysis through the upregulation of Src, mTOR and FAK. In addition, we found that nNOS participates actively in PV at least in part by increasing caspase-9 and caspase-3 activities. These findings underline the important issue that in PV acantholysis, caspase activation is a nNOS-linked process downstream of Src, mTOR and FAK kinase upregulation.
Department of Dermatology, University Clinic of Navarra, School of Medicine, University of Navarra, Navarra, Spain. aespana@unav.es
Agustín
A
España
Teresa
T
Mòdol
Maria P
MP
Gil
Maria J
MJ
López-Zabalza
D000051:Acantholysis / Q000201:enzymology*; D000818:Animals; D001706:Biopsy; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010392:Pemphigus / Q000201:enzymology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism*
D007074:Immunoglobulin G; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C546843:mTOR protein, mouse; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; D058570:TOR Serine-Threonine Kinases; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9