| First Author | Guzmán-Mejía F | Year | 2018 |
| Journal | J Neuroimmune Pharmacol | Volume | 13 |
| Issue | 1 | Pages | 39-52 |
| PubMed ID | 28822039 | Mgi Jnum | J:328385 |
| Mgi Id | MGI:6844468 | Doi | 10.1007/s11481-017-9760-7 |
| Citation | Guzman-Mejia F, et al. (2018) Stimulation of nAchRalpha7 Receptor Inhibits TNF Synthesis and Secretion in Response to LPS Treatment of Mast Cells by Targeting ERK1/2 and TACE Activation. J Neuroimmune Pharmacol 13(1):39-52 |
| abstractText | The cholinergic anti-inflammatory pathway is recognized as one of the main mechanisms of neuromodulation of the immune system. Activation of the alpha7 nicotinic acetylcholine receptor (nAchRalpha7) suppresses cytokine synthesis in distinct immune cells but the molecular mechanisms behind this effect remain to be fully described. Mast cells (MCs) are essential players of allergic reactions and innate immunity responses related to chronic inflammation. Activation of TLR4 receptor in MCs leads to the rapid secretion of pre-synthesized TNF from intracellular pools and to the activation of NFkappaB, necessary for de novo synthesis of TNF and other cytokines. Here we report that the nAchRalpha7 receptor specific agonist GTS-21 inhibits TLR4-induced secretion of preformed TNF from MCs in vivo and in vitro. Utilizing bone marrow-derived mast cells (BMMCs) it was found that GTS-21 also diminished secretion of de novo synthesized TNF, TNF mRNA accumulation and IKK-dependent p65-NFkappaB phosphorylation in response to LPS. nAchRalpha7 triggering prevented TLR4-induced ERK1/2 phosphorylation, which resulted an essential step for TNF secretion due to the phosphorylation of the metallopeptidase responsible for TNF maturation (TACE). Main inhibitory actions of GTS-21 were prevented by AG490, an inhibitor of JAK-2 kinase. Our results show for the first time, that besides the prevention of NFkappaB-dependent transcription, inhibitory actions of nAchRalpha7 triggering include the blockade of pathways leading to exocytosis of granule-stored cytokines in MCs. |
