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  • The role of nitric oxide synthases in pemphigus vulgaris in a mouse model.

The role of nitric oxide synthases in pemphigus vulgaris in a mouse model.

The British journal of dermatology (2008-05-15)
M Marquina, A España, M Fernández-Galar, M J López-Zabalza
ABSTRACT

Pemphigus vulgaris (PV) is a blistering autoimmune disease characterized by IgG autoantibodies against desmoglein 3. Nitric oxide synthases (NOS) may contribute to the increase of inflammation in tissues by the generation of nitrotyrosine residues (NTR). To investigate whether the production of NTR mediated by NOS may participate in the development of inflammation and acantholysis in PV. Mice were pretreated or not with NOS, tyrosine-kinase (TK) or nuclear factor (NF)-kappaB inhibitors, and then injected with PV-IgG. PV manifestations were examined in all mice. The expression of NTR, constitutive NOS (cNOS) [endothelial NOS (eNOS) and neuronal NOS (nNOS)], inducible NOS (iNOS) and NF-kappaB factor were studied in epidermis of mice using immunohistochemical techniques. After PV-IgG injection, expressions of NTR, iNOS, eNOS and nNOS increased in acantholytic cells, as did nuclear translocation of NF-kappaB in the basal cells of the epidermis. Pretreatment of mice with inhibitors of TK, nNOS and nonselective NOS, completely prevented NTR expression and the clinical and histological findings of PV in mice. TK inhibitor genistein inhibited both nNOS and iNOS expression on the membrane of basal keratinocytes, and nuclear translocation of NF-kappaB. Upregulation of cNOS and iNOS, NTR generation and nuclear translocation of NF-kappaB may contribute to increased inflammation and tissue damage in PV lesions. The absence of the clinical and histological findings of PV and NTR expression in mice injected with PV-IgG, through pretreatment with TK and nNOS inhibitors, provides compelling evidence that these signalling molecules should be considered as potential therapeutic targets in PV.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
NG-Monomethyl-L-arginine, Monoacetate Salt, Cell permeable. L-Arginine analog that acts as a competitive inhibitor of all three isoforms of NOS.
Millipore
S-Methyl-L-thiocitrulline, Dihydrochloride, A cell-permeable inhibitor of nitric oxide synthase that exhibits about 17-fold greater selectivity for rat neuronal nitric oxide synthase (IC₅₀ = 300 nM) compared to the endothelial enzyme (IC₅₀ = 5.4 µM).
Sigma-Aldrich
Genistein, synthetic, ≥98% (HPLC), powder
Sigma-Aldrich
Anti-Nitric Oxide Synthase I Antibody, Chemicon®, from rabbit
Sigma-Aldrich
1400W, A selective, cell-permeable, irreversible, slow, tight-binding inhibitor of inducible nitric oxide synthase (iNOS; Kd = 7 nM).
Sigma-Aldrich
L-N⁵-(1-Iminoethyl)ornithine, Dihydrochloride, A cell-permeable, more potent inhibitor of endothelial nitric oxide synthase compared to other arginine analogs such as L-NAME and L-NMMA.
Sigma-Aldrich
Parthenolide, Tanacetum parthenium, A cell-permeable sesquiterpene lactone with anti-inflammatory, antisecretory, and spasmolytic properties.