Soluble tumor necrosis factor receptors are released independent of TNF in endotoxemia

The pathway by which the in vivo application of LPS induces the release of soluble TNF receptor molecules (sTNF-R) is not yet understood. Earlier findings have demonstrated that the injection of LPS induces the release of TNFα, and injections of TNFα induce sTNF-R I and II. Thus one would assume that sTNF-R are released after LPS application as a result of endogenous production of TNFα. In this study, i.v. bolus injections of Salmonella abortus equi endotoxin (4 ng/kg body weight) once daily for 5 consecutive days were administered to cancer patients. The time course of serum levels of TNFα and sTNF-R I and II were determined. sTNF-R I and II were released after every LPS injection with peak levels being comparable on days 1 through 5. In contrast, the TNFα peak level on day 1 was about 50 times higher than on day 2. On days 3 through 5, no TNFα could be detected, a phenomenon referred to as endotoxin tolerance. Since LPS was able to provoke a comparable release of sTNF-R despite inducing widely differing levels of TNF-α, we conclude that the release of sTNF-R I and II during endotoxemia is not induced via TNF-α.