Preconditioning up-regulates the soluble TNF receptor 1 response to endotoxin

Background. Sepsis and endotoxemia frequently complicate the care of surgical patients. Basic and clinical investigations have correlated tumor necrosis factor alpha (TNF) levels with myocardial suppression and lethality after sepsis. Soluble TNF receptor 1 (sTNFRI) is an endogenous mechanism of clearing serum TNF. Elucidating mechanisms of endogenous adaptation may allow the development of novel therapeutic strategies. Endotoxin tolerance (LPS-preconditioning) is associated with a down-regulation of proinflammatory monokine production; thus, similar down-regulation of sTNFRI may be expected. However, it may be equally plausible to hypothesize that the processes which lead to enhanced shedding of these receptors A are up-regulated during tolerance. Materials and methods. To study this, sublethal LPS was administered to male rats (Salmonella typhimurium, 500 mug/kg IP in 1 ml bacteriostatic normal saline IP) or an equivalent volume of bacteriostatic normal saline IP (sham) 24 h prior to subsequent LPS challenge. Rats were sacrificed at 0, 1, 2, 4, 6, and 24 h following LPS and serum TNF and TNYRI were measured by ELISAs. Results. LPS induced a significant increase in sTNFRI at 1, 2,4, and 6 h following LPS. sTNFRI levels returned to baseline by 24 h following LPS treatment. LPS induced a parallel increase in TNF. LPS pretreatment (preconditioning) resulted in a significant increase in TNFRI and a significant decrease in TNF. Conclusion. This study constitutes the initial demonstration that tolerance mechanisms: (1) up-regulate sTNFRI, which binds and clears TNF; and (2) reverses the TNF-to-sTNFRI ratio. Safe pharmacologic methods of up-regulating endogenous TNF-clearance mechanisms may ultimately have therapeutic value. (C) 2004 Elsevier Inc. All rights reserved.