Epinephrine and endotoxin tolerance differentially modulate serum cytokinelevels to high-dose lipopolysaccharide challenge in a murine model

Background. The epinephrine tolerance state has been demonstrated to increa se survival in endotoxic shock and was claimed to have cross-tolerance with endotoxin tolerance. With use of these data, we aimed to determine the eff ect of epinephrine and endotoxin tolerance on major cytokine levels in a li popolysaccharide challenge in mice. Methods. Epinephrine tolerance was induced by beginning with a low dose and gradually increasing to a lethal dose. Endotoxin tolerance was induced by injecting saline solution for 4 days and lipopolysaccharide 1 mg/kg on the fifth day. After these procedures, saline solution or 20 mg/kg lipopolysacc haride was injected into animals. Peak serum levels of tumor necrosis facto r-alpha (TNF-alpha), interleukin 1 beta, interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 12 (IL-12) were assayed. Results. The lipopolysaccharide injection increased the levels of all the c ytokines in the control and epinephrine-tolerant animals. TNF-alpha, IL-6, and IL-10 levels were lower in endotoxin-tolerant animals compared with con trols. Epinephrine-tolerant animals had higher levels of TNF-alpha, IL-6, a nd IL-12 than the controls did. Conclusion. Epinephrine tolerance primes for an exaggerated release of TNF- alpha, IL-6, and IL-12 in response to lipopolysaccharide challenge, suggest ing anti-inflammatory and immunosuppressive effects by epinephrine. The ant i-inflammatory effect was not mediated through increased IL-10 release. End otoxin tolerance selectively modulated cytokine release.