| First Author | Garg BK | Year | 2019 |
| Journal | PLoS One | Volume | 14 |
| Issue | 4 | Pages | e0214942 |
| PubMed ID | 30947238 | Mgi Jnum | J:274605 |
| Mgi Id | MGI:6293992 | Doi | 10.1371/journal.pone.0214942 |
| Citation | Garg BK, et al. (2019) GTS-21 has cell-specific anti-inflammatory effects independent of alpha7 nicotinic acetylcholine receptors. PLoS One 14(4):e0214942 |
| abstractText | alpha7 Nicotinic acetylcholine receptors (nAChRs) reportedly reduce inflammation by blocking effects of the important pro-inflammatory transcription factor, nuclear factor kappa-light chain-enhancer of B cells (NFkappaB). The alpha7 nAChR partial agonist GTS-21 reduces secretion of pro-inflammatory cytokines including interleukin-6 (IL6) and tumor-necrosis factor (TNF) in models of endotoxemia and sepsis, and its anti-inflammatory effects are widely ascribed to alpha7 nAChR activation. However, mechanistic details of alpha7 nAChR involvement in GTS-21 effects on inflammatory pathways remain unclear. Here, we investigate how GTS-21 acts in two cell systems including the non-immune rat pituitary cell line GH4C1 expressing an NFkappaB-driven reporter gene and cytokine secretion by ex vivo cultures of primary mouse macrophages activated by lipopolysaccharide (LPS). GTS-21 does not change TNF-stimulated NFkappaB signaling in GH4C1 cells expressing rat alpha7 nAChRs, suggesting that GTS-21 requires additional unidentified factors besides alpha7 nAChR expression to allow anti-inflammatory effects in these cells. In contrast, GTS-21 dose-dependently suppresses LPS-induced IL6 and TNF secretion in primary mouse macrophages endogenously expressing alpha7 nAChRs. GTS-21 also blocks TNF-induced phosphorylation of NFkappaB inhibitor alpha (IkappaBalpha), an important intermediary in NFkappaB signaling. However, alpha7 antagonists methyllycaconitine and alpha-bungarotoxin only partially reverse GTS-21 blockade of IL6 and TNF secretion. Further, GTS-21 significantly inhibited LPS-induced IL6 and TNF secretion in macrophages isolated from knockout mice lacking alpha7 nAChRs. These data indicate that even though a discrete component of the anti-inflammatory effects of GTS-21 requires expression of alpha7 nAChRs in macrophages, GTS-21 also has anti-inflammatory effects independent of these receptors depending on the cellular context. |
