INDUCTION OF PLASMA INHIBITORS OF INTERLEUKIN-1 AND TNF-ALPHA ACTIVITY BY ENDOTOXIN ADMINISTRATION TO NORMAL HUMANS

Several naturally occurring inhibitors of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) have been demonstrated both in serum and urine of febrile patients. These factors are considered to be part of a regulatory system counteracting potential deleterious effects of the cytokines. We have assayed plasma samples of volunteers who received a bolus intravenous injection of either 4 ng/kg body wt of Escherichia coli endotoxin (n = 6) or 0.9% saline (n = 4) for the presence of IL-1 and TNF-alpha inhibitory activity. Plasma obtained 3 h after endotoxin injection inhibited IL-1-induced PGE2 release from fibroblasts by 57% (P < 0.001 vs. baseline and saline controls, respectively). Maximal IL-1 inhibitory capacity coincided with fever and tended to disappear with declining body temperature. Normal plasma was found to inhibit TNF-alpha-induced PGE2 release by 20-35%. This inhibitory effect increased to 50-60% in plasma obtained during endotoxinemia. Maximal TNF-alpha inhibitory capacity became detectable when circulating TNF-alpha levels peaked at 120 min after the injection of endotoxin. Our data demonstrate that both IL-1 and TNF-alpha inhibitory activity can be induced experimentally by intravenous endotoxin administration to humans and that their appearance coincides with fever and circulating TNF-alpha levels.