Bucillamine Induces the Synthesis of Vascular Endothelial Growth Factor Dose-Dependently in Systemic Sclerosis Fibroblasts via Nuclear Factor-JB and Simian Virus 40 Promoter Factor 1

The pathogenesis of systemic sclerosis (SSc) is characterized by activation of the immune system, impaired angiogenesis, and activated dermal fibroblasts. The effects of the immunosuppres-sive agent bucillamine (SA 96) on fibroblasts and angiogenic fac-tors have not been examined. SA 96, and particularly its metab-olite 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)-B signal-ing with pyrrolidine dithiocarbamate treatment and IB transfec-tion reduced significantly the transcription of VEGF, indicating tha