Combined inhibition of interleukin-1 and tumor necrosis factor in rodent endotoxemia: improved survival and organ function.

Abstract

The interleukin (IL)-1 receptor antagonist (Ra) and a polyethylene glycol-linked dimer of the type I soluble receptor of tumor necrosis factor (TNF), PEG-(rsTNF-RI)2, were used to determine whether maximal protection against lethality and organ dysfunction is achieved by single or dual cytokine inhibition under rigorous conditions of rodent endotoxemia. Inhibition of IL-1 or TNF alone protected maximally against lethality when inhibitors were given simultaneously with lipopolysaccharide (LPS) under minimal lethal conditions. Combined inhibition of IL-1 and TNF was necessary to maximally protect against lethality when treatment was delayed until 7 h after LPS injection under minimal lethal conditions or when treatment was begun immediately after LPS injection under supralethal conditions. Improved survival in IL-1Ra- plus PEG-(rsTNF-RI)2-treated rats was associated with enhanced protection against renal and metabolic dysfunctions. Thus, under very severe conditions of endotoxemia, TNF and IL-1 may act independently to mediate lethality and some organ dysfunctions.