Combined Inhibition of Interleukin-1 and Tumor Necrosis Factor in Rodent Endotoxemia: Improved Survival and Organ Function

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Abstract
The interleukin (IL)-l 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-l or TNF alone protected maximally against lethality when inhibitors were given simultaneously with lipopolysaccharide (LPS) under minimal lethal conditions. Combined inhibition of IL-l 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-l may act independently to mediate lethality and some organ dysfunctions.

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