Endotoxin-tolerant mice produce an inhibitor of tumor necrosis factor synthesis

Abstract

The present study was carried out to investigate a new aspect of early endotoxin tolerance in mice. Evidence was obtained that early endotoxin tolerance is associated with the production of an activity interfering with the synthesis of tumor necrosis factor α (TNFα). LPS-tolerant mice, challenged with lipopolysaccharide (LPS) had lower serum levels of TNF than LPS-treated normal animals. In parallel, whole blood of tolerant mice, treated with LPS ex vivo generated lower levels of TNF than blood of normal animals. Plasma obtained 30 min after challenge with LPS from tolerant mice was inhibitory for TNF synthesis in whole blood of normal mice ex vivo. This seems to be specific for tolerant mice, since plasma prepared from normal, endotoxin-challenged mice was devoid of inhibitory activity for TNF production. The TNF-inhibitor in plasma of endotoxin tolerant mice did not interfere with the cytotoxic activity of murine recombinant TNFα on WEHI cells. Heat treatment of plasma destroyed the activity.