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Genotype-dependent NOS-3 expression and rheumatoid arthritis
Arthritis Research & Therapyvolume 7, Article number: P104 (2005)
The -786C-variant of the endothelial nitric oxide synthase nos-3 gene has been shown to be associated with coronary artery disease because of a blunted inducibility of gene expression . IL-10, a cytokine involved in TH1/TH2-cell differentiation, is a new stimulus for NOS-3 expression .
We here address the question whether IL-10-induced NOS-3 expression is decreased in individuals with the -786C/C genotype and, if so, whether a TH1-mediated disease like rheumatoid arthritis is associated with this genotype.
Endothelial cells were isolated from an umbilical cord vein of known genotype and cultured as described . The expression of NOS-3 was analysed by real-time semi-quantitative RT-PCR . Genotyping was performed as described elsewhere . Patients met the revised criteria of the ACR for the classification of rheumatoid arthritis, and donated blood samples after informed consent.
Primary human umbilical vein endothelial cells with the -786C/C genotype did not respond with an increase in NOS-3 expression to IL-10 incubation (5 ng/ml). This defect could be repaired after pre-incubation of the cells with a decoy oligonucleotide (10 μmol/l) directed against the C-variant of the promoter. Among 587 patients with rheumatoid arthritis tested, incidences for the -786C/C genotype were significantly higher than in the general population (17% versus 11.7%; P < 0.01).
NOS-3 is one mediator of anti-inflammatory IL-10 actions. Individuals with the -786C/C nos-3-genotype have an increased risk for the development of rheumatoid arthritis. This might be due to the IL-10 insensitivity of the C-variant of the promoter.
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Supported by a grant of the BMBF (competence network rheumatism) to IM.