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


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 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.


RESULTS
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.


CONCLUSIONS
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.
Baykal
A
A
Department of General Surgery, Hacettepe University School of Medicine, Ankara, Turkey.
Kaynaroglu
V
V
Hascelik
G
G
Sayek
I
I
Sanac
Y
Y
D000818:Animals; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004837:Epinephrine / Q000494:pharmacology*; D007375:Interleukin-1 / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D012769:Shock / Q000276:immunology* / Q000378:metabolism; D013312:Stress, Physiological / Q000276:immunology* / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D013566:Sympathomimetics; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D004837:Epinephrine