GTS-21 (E-3-(2,4)-dimethoxybenzylidene anabaseine) is a highly specific α7nAchR agonist, that has been developed for the treatment of Alzheimer's disease that has been studied in a few inflammation-related models. In a murine pancreatitis model pre-treatment of the animals with GTS-21 decreased pancreatitis severity and was associated with reduced IL-6 levels and decreased pancreatic neutrophil accumulation (11). Pre-treatment of mice with GTS-21 attenuated systemic TNF concentrations after injection with LPS and increases survival (12,13). Similarly, GTS-21 inhibited blood levels of the inflammatory mediator High Mobility Group Box 1 (HMGB1) and improved survival of mice after cecal ligation and puncture.(13). Recently, we have shown that stimulation of the α7nAChR by the highly selective agonist GTS-21 leads to a dramatic dose-dependent inhibition of pro-inflammatory cytokine release induced by stimulation of various Toll-like receptors (TLR) in human whole blood (Kox et al, submitted). This inhibitory effect of GTS-21 was not specific for the TLR-agonist used and GTS-21 inhibited pro-inflammatory cytokine production stronger than nicotine at equimolar concentrations. Moreover, the production of the anti-inflammatory cytokine IL-10 was not inhibited, but even significantly stimulated. Therefore, stimulation of the α7nAChR by GTS-21 results in a profound anti-inflammatory shift of the pro-/anti-inflammatory balance. So far, no data are available on the anti-inflammatory effects of GTS-21 in humans in vivo.