The role of tumor necrosis factor (TNF) in interleukin (IL)-8 release in septicemia in the baboon (2-h infusion of live Escherichia coli, 5 x 10(8) cfu/kg) was investigated. Four experiments were done: one control (n = 7) and three with pretreatment to reduce TNF plasma levels. Pretreatment was with anti-TNF antibody (anti-TNF) 15 mg/kg, which neutralized circulating TNF (n = 4); 0.5 mg/kg of anti-TNF, which reduced peak TNF from 6.2 ng/mL (controls) to 0.6 ng/mL (n = 4); and a xanthine derivate (HWA138), which reduced TNF to 1 ng/mL (n = 5). With TNF levels < 1 ng/mL, a significant reduction of circulating IL-8 from 10.4 ng/mL (peak) in controls to 1 ng/mL (peak) in anti-TNF-treated animals was found, but with HWA138 only some decrease in IL-8 was seen. Despite high endotoxin levels (10-30 ng/mL peak), neutralization of TNF resulted in diminished release of IL-8 and significantly lower levels of granulocyte elastase.