Abstract
Background and Methods
To assess whether gold-containing disease-modifying antirheumatic drugs influenced the ability of human polymorphonuclear granulocytes (PMN) or nitric oxide (NO) to cause injury to human umbilical vein endothelial cells (HUVEC) in vitro (measured as release of 51Cr) after HUVEC had been activated with interleukin-1β (IL-1β) or tumor necrosis factor alpha (TNF-α).
Results
IL-1β and TNF-α caused a prominent PMN-mediated 51Cr release that was dose-dependently reduced when auranofin (AF) or gold sodium aurothiomalate (GSTM) were added to PMN and HUVEC in the assay system. This protective effect remained, with stimulus- and drug-specific variations, when HUVEC alone were treated with the drugs. Likewise, when HUVEC cytotoxicity was induced by exogenous NO (donated by S-nitroso-acetyl-penicillamine [SNAP]), AF and GSTM inhibited the injury significantly. Some observations indicated that PMN agonists, generated by TNF-α-activated HUVEC (eg, IL-8), were modulated by the antirheumatic drugs. First, addition of AF, but not GSTM, reduced the generation of IL-8 by 65%. Secondly, TNF-α-activated HUVEC triggered a rapid, transient rise of cytosolic Ca2+ concentrations in previously quiescent PMN; this rise was obliterated by prior treatment of HUVEC with AF (but not with GSTM). When TNF-α-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 reduced IL-1β- and TNF-α-induced and PMN-dependent HUVEC injury by interfering with intercellular signaling systems and cytoxicity conferred by NO and PMN granula constituents. (J Investig Med 2000;48:395–402)
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