Lipopolysaccharide upregulates α7 acetylcholine receptors: stimulation with GTS-21 mitigates growth arrest of macrophages and improves survival in burned mice.

Nicotinic stimulation of the alpha7 acetylcholine receptors (α7AChRs) mitigates the lipopolysaccharide (LPS)-induced TNF-α and other cytokines release in macrophages. This effect is blocked by α7AChR antagonist, α-bungarotoxin (BTX). We tested and confirmed the hypotheses that LPS up-regulates α7AChRs and the prototypical α7AChR antagonists, vecuronium, and BTX do not block the effects of GTS-21, a specific α7AChR agonist, on TNF-α release. With the knockdown of α7AChR expression by siRNA, GTS-21 effects on inhibition of TNF-α release were not demonstrable. In addition, GTS-21 mitigated the LPS-induced growth arrest of macrophages in vitro in J774A.1 cells and ex vivo in peritoneal macrophages obtained from mice at three days after burn. Moreover, GTS-21 reduced mortality after burn injury in mice. These results indicate that (i) LPS up-regulates α7AChRs; (ii) the therapeutic beneficial effects of GTS-21 on cytokine release are specifically mediated via α7AChRs and are preserved even when co-treated with prototypical antagonist, BTX, or clinically used muscle nicotinic antagonist, vecuronium; (iii) activation of α7AChRs by GTS-21 partially reverses the LPS-induced proliferation arrest and (iv) GTS-21 reduces mortality in mice with burn injury. The in vivo beneficial effects of GTS-21 in burn injury warrant further studies.