PT  - JOURNAL ARTICLE
AU  - Jörg H. W. Distler
AU  - Claudia Hagen
AU  - Astrid Hirth
AU  - Ulf Müller-Ladner
AU  - Hanns M. Lorenz
AU  - Angela del Rosso
AU  - Beat A. Michel
AU  - Renate E. Gay
AU  - Ratanavadee Nanagara
AU  - Kusuki Nishioka
AU  - Marco Matucci-Cerinic
AU  - Joachim R. Kalden
AU  - Steffen Gay
AU  - Oliver Distler
TI  - Bucillamine Induces the Synthesis of Vascular Endothelial Growth Factor Dose-Dependently in Systemic Sclerosis Fibroblasts via Nuclear Factor-κB and Simian Virus 40 Promoter Factor 1 Pathways
AID  - 10.1124/mol.65.2.389
DP  - 2004 Feb 01
TA  - Molecular Pharmacology
PG  - 389--399
VI  - 65
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/65/2/389.short
4100  - http://molpharm.aspetjournals.org/content/65/2/389.full
SO  - Mol Pharmacol2004 Feb 01; 65
AB  - The pathogenesis of systemic sclerosis (SSc) is characterized by activation of the immune system, impaired angiogenesis, and activated dermal fibroblasts. The effects of the immunosuppressive agent bucillamine (SA 96) on fibroblasts and angiogenic factors have not been examined. SA 96, and particularly its metabolite SA 981, increased the levels of vascular endothelial growth factor (VEGF) mRNA and protein dose-dependently in dermal fibroblasts from patients with SSc and healthy control subjects without influencing cell viability. SSc fibroblast cultures showed consistently a higher inducibility of VEGF than cultures from healthy control subjects. Preincubation with the SP-1 inhibitor mithramycin as well as blockade of nuclear factor (NF)-κB signaling with pyrrolidine dithiocarbamate treatment and IκB transfection reduced significantly the transcription of VEGF, indicating that both transcription factors contribute to the activation of VEGF by SA 981. Specific binding of NF-κB protein to its binding site after treatment with SA 981 was confirmed by electrophoretic mobility shift assay. In contrast, SA 981 did not influence the stability of VEGF mRNA as analyzed with actinomycin D assays. The study provides evidence for a role of NF-κB in the transcriptional regulation of the VEGF gene. SA 96 might have positive aspects on the impaired angiogenesis in patients with SSc.