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GTS-21 has cell-specific anti-inflammatory effects independent of ?7 nicotinic acetylcholine receptors.

ABSTRACT: ?7 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 (NF?B). The ?7 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 ?7 nAChR activation. However, mechanistic details of ?7 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 NF?B-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 NF?B signaling in GH4C1 cells expressing rat ?7 nAChRs, suggesting that GTS-21 requires additional unidentified factors besides ?7 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 ?7 nAChRs. GTS-21 also blocks TNF-induced phosphorylation of NF?B inhibitor alpha (I?B?), an important intermediary in NF?B signaling. However, ?7 antagonists methyllycaconitine and ?-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 ?7 nAChRs. These data indicate that even though a discrete component of the anti-inflammatory effects of GTS-21 requires expression of ?7 nAChRs in macrophages, GTS-21 also has anti-inflammatory effects independent of these receptors depending on the cellular context.


PROVIDER: S-EPMC6448884 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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