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Synthesis and secretion of proinflammatory mediators like tumor necrosis factor–α and neopterin are common events in severe systemic inflammatory disorders, e.g. sepsis and septic shock. Recent data suggest that both substances show similarities with respect to their bioactivities. In the present study we investigated the potential interactions of neopterin and tumor necrosis factor–α on inducible nitric oxide synthase gene expression and nitric oxide generation in rat vascular smooth muscle cells. In addition, we studied the influence of neopterin on tumor necrosis factor–α synthesis in this cell type. Single stimulation of smooth muscle cells with either neopterin or tumor necrosis factor–α caused inducible nitric oxide synthase gene expression and nitric oxide production. Coincubation of cells with both compounds resulted in at least additive effects on nitric oxide synthesis. Quantification of tumor necrosis factor–α cDNA revealed a dose–dependent effect of neopterin on tumor necrosis factor–α gene expression. Similar results were obtained concerning the detection of tumor necrosis factor–α protein and the assessment of tumor necrosis factor–α bioactivity. These data suggest that neopterin and tumor necrosis factor–α are closely associated with regard to synthesis and effects, respectively. The interactions of both inflammatory mediators in vascular smooth muscle cells might contribute to the excessive release of nitric oxide observed during sepsis, thus triggering cellular destruction and multiple organ failure. [ABSTRACT FROM AUTHOR]