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

Abstract

The epinephrine tolerance state has been demonstrated to increase survival in endotoxic shock and was claimed to have cross-tolerance with endotoxin tolerance. With use of these data, we aimed to determine the effect of epinephrine and endotoxin tolerance on major cytokine levels in a lipopolysaccharide challenge in mice. 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 lipopolysaccharide was injected into animals. Peak serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta, interleukin 6 (IL-6), interleukin 10 (IL-10), and interleukin 12 (IL-12) were assayed. The lipopolysaccharide injection increased the levels of all the cytokines in the control and epinephrine-tolerant animals. TNF-alpha, IL-6, and IL-10 levels were lower in endotoxin-tolerant animals compared with controls. Epinephrine-tolerant animals had higher levels of TNF-alpha, IL-6, and IL-12 than the controls did. Epinephrine tolerance primes for an exaggerated release of TNF-alpha, IL-6, and IL-12 in response to lipopolysaccharide challenge, suggesting anti-inflammatory and immunosuppressive effects by epinephrine. The anti-inflammatory effect was not mediated through increased IL-10 release. Endotoxin tolerance selectively modulated cytokine release.