Differential contribution of beta-adrenergic receptors expressed on radiosensitive versus radioresistant cells to protection against inflammation and mortality in murine endotoxemia.

The sympathetic nervous system modulates immune responses via the secretion of catecholamines and subsequent activation of adrenergic receptors (ARs), and systemic catecholamine levels increase markedly in the setting of endotoxemia and sepsis. Previous studies have demonstrated that stimulation of beta-ARs by pharmacological agonists attenuates the inflammatory response to LPS observed in vitro and can increase survival in animal models of endotoxemia and sepsis. However, the consequences of beta-AR activation by endogenous catecholamines have not been explored in these settings. Furthermore, the relative contribution of beta-ARs expressed on immune versus nonimmune cells to LPS-mediated inflammation and mortality is not known. Our first goal was therefore to determine the impact of beta-AR stimulation by endogenous catecholamines released during endotoxemia on LPS-mediated inflammation and mortality in vivo. To address this question, we examined the LPS response of mice lacking all three known betaAR subtypes, beta1-, beta2-, and beta3-AR, and demonstrated that these beta-less mice exhibited a net increase in inflammation (increased TNF-alpha levels and decreased IL-10 levels in serum) and a 50% decrease in survival relative to wild-type animals. The second goal of our study was to determine the relative contribution of beta-ARs expressed on radiosensitive immune versus radioresistant cells to the protective action of beta-ARs in the setting of endotoxemia. We therefore examined the LPS response of bone marrow chimeras generated between beta-less and wild-type mice, and concluded that beta-ARs expressed on radioresistant cells play the dominant role in protecting against LPS-mediated mortality and attenuating systemic TNF-alpha responses. Finally, we determined that beta3-AR subtype does not play a significant role in regulating LPS-mediated mortality and inflammation by evaluating mice lacking the beta1- and beta2-AR subtypes only.