Lipopolysaccharide upregulates α7 acetylcholine receptors: stimulation with GTS-21 mitigates growth arrest of macrophages and improves survival in burned mice.
Nicotinic stimulation of the α7 acetylcholine receptors (α7AChRs) mitigates the lipopolysaccharide (LPS)-induced tumor necrosis factor α (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 upregulates 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 short interference RNA, 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 3 days after burn. Moreover, GTS-21 reduced mortality after burn injury in mice. These results indicate that (i) LPS upregulates α7AChRs; (ii) the therapeutic beneficial effects of GTS-21 on cytokine release are specifically mediated via α7AChRs and are preserved even when cotreated 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.
Department of Anesthesia, Critical Care and Pain Medicine, Shriners Hospitals for Children®, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Mohammed Abdul Sattar
MA
Khan
Mina
M
Farkhondeh
Jennifer
J
Crombie
Leslie
L
Jacobson
Masao
M
Kaneki
J A Jeevendra
JA
Martyn
D000704:Analysis of Variance; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002038:Bungarotoxins / Q000494:pharmacology; D002056:Burns / Q000401:mortality*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; D002038:Bungarotoxins; C579166:Chrna7 protein, mouse; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; D011725:Pyridines; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine