A bacteria-induced switch of sympathetic effector mechanisms augments local inhibition of TNF-alpha and IL-6 secretion in the spleen

It is believed that an inflammation-induced activation of the CNS leads to an inhibition of overshooting immune responses to prevent extensive local c ytokine secretion. However, immunosuppression by the sympathetic nervous sy stem may be unfavorable when bacteria are present locally and when TNF-alph a is necessary to overcome infection. We now report in a superfusion model, using mouse spleen slices, that although local Pseudomonas aeruginosa incr eased splenic TNF-alpha and IL-6 secretion severalfold over basal levels, e lectrically released neurotransmitters attenuated cytokine secretion to sim ilar basal level as under bacteria-free conditions. Bacteria reversed norad renergic inhibitory effector mechanisms: Under bacteria-free conditions, TN F-alpha secretion was very low and IL-6 secretion was mainly inhibited by a lpha(2)-adrenoreceptor ligation. In the presence of bacteria, TNF-alpha and IL-6 secretion were high and IL-6 secretion was mainly inhibited by beta-a drenoreceptor ligation. The alpha- to beta-adrenoswitch of IL-6 inhibition in the presence of bacteria was mediated by the prior adrenergic regulation of TNF-alpha. In vivo, chemical abrogation of sympathetic inhibition reduc ed accumulation of bacteria in the spleen, which depended at least in part on TNF-alpha. This suggests that activation of the sympathetic nervous syst em may be a forerunner for accumulation of bacteria in tissue and consecuti vely sepsis due to intensified inhibition of TNF-alpha secretion.