Effects of antirheumatic gold salts on cytokine-induced neutrophil-dependent cytotoxicity for human endothelial cells

Background and Methods: To assess whether gold-containing disease-modifying antirheumatic drugs influenced the ability of human polymorphonuclear gran ulocytes (PMN) or nitric oxide (NO) to cause injury to human umbilical vein endothelial cells (HUVEC) in vitro (measured as release of Cr-51) after HU VEC had been activated with interleukin-1 beta (IL-1 beta) or tumor necrosi s factor alpha (TNF-alpha), Results: IL-1 beta and TNP-alpha caused a prominent PMN-mediated Cr-51 rele ase that was dose-dependently reduced when auranofin (AF) or gold sodium au rothiomalate (GSTM) were added to PMN and HUVEC in the assay system. This p rotective effect remained, with stimulus- and drug-specific variations, whe n HUVEC alone were treated with the drugs. Likewise, when HUVEC cytotoxicit y was induced by exogenous NO (donated by S-nitroso-acetyl-penicillamine [S NAP]), AF and GSTM inhibited the injury significantly. Some observations in dicated that PMN agonists, generated by TNF-alpha -activated HUVEC leg, IL- 8), were modulated by the antirheumatic drugs. First, addition of AF, but n ot GSTM, reduced the generation of IL-8 by 65%, Secondly, TNF-alpha -activa ted HUVEC triggered a rapid, transient rise of cytosolic Ca2+ concentration s in previously quiescent PMN; this rise was obliterated by prior treatment of HUVEC with AF (but not with GSTM), When TNF-alpha -induced endothelial cytotoxicity was provoked by PMN lysates, AF and GSTM inhibited this injury significantly. Conclusions: Thus, in this in vitro model of vasculitis, AF and GSTM reduce d IL-1 beta- and TNF-alpha -induced and PMN-dependent HUVEC injury by inter fering with intercellular signaling systems and cytoxicity conferred by NO and PMN granula constituents.