Enhanced adrenergic stimulation and catecholamine release are important components of the pathophysiology of sepsis. Under physiologic conditions, adrenergic stimulation has been shown to be a negative regulator of pro-inflammatory cytokine production through increasing IL-10 production. Here we have investigated if adrenergic stimulation similarly inhibits TNF- and IL-6 production by splenic macrophages isolated from a polymicrobial sepsis model. Male B6D2F1 mice were subjected to Sham (S), Laparotomy (L) and Cecal Ligation and Puncture (CLP) under anesthesia. Splenic macrophages were isolated 72 h after the initial injury and were stimulated with endotoxin (LPS) in the presence and absence of epinephrine. Compared to S and L, splenic macrophage from the CLP group produced significantly less TNF- and IL-6 and more IL-10 when stimulated with LPS. Macrophage cultures from CLP animals incubated with either epinephrine or IL-10 for 2 h had significantly reduced TNF- and IL-6 release in response to LPS. However, similar cultures pre-treated with IL-10 antibody prior to addition of exogenous epinephrine failed to reverse the attenuation of LPS-stimulated cytokines. Pre-treatment of macrophage cultures with ₂ (ICI-118551) but not ₁ (atenolol) adrenergic receptor antagonists reversed the epinephrine-mediated cytokine attenuation following LPS treatment. These results suggest that adrenergic mechanisms may influence peripheral tissue macrophage inflammatory cytokine response following trauma and sepsis independent of the effects of IL-10.