Cynandione A and PHA-543613 inhibit inflammation and stimulate macrophageal IL-10 expression following α7 nAChR activation

• Published in: Biochemical pharmacology 2021-08, Vol.190, p.114600-114600, Article 114600
• Main Authors: Han, Qiao-Qiao, Deng, Meng-Yan, Liu, Hao, Ali, Usman, Li, Xin-Yan, Wang, Yong-Xiang
• Format: Article
• Language: English
• Subjects: Antiinflammation; Cynandione A; Interleukin-10 (IL-10); Macrophage; PHA-543613; α7 Nicotinic acetylcholine receptor (α7 nAChR)
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2021.114600

[Display omitted] Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, attenuates inflammation. The present study aimed to study the mechanisms underlying cynandione A-induced antiinflammation. Treatment with cynandione A and the specific α7 nicotinic acetylcholine receptor (α7 nAChR) agonist PHA-543613 remarkably reduced overexpression of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in lipopolysaccharide (LPS)-treated RAW264.7 cells and primary peritoneal macrophages, and endotoxemic mice. Both cynandione A and PHA-543613 also stimulated IL-10 expression in naïve and LPS-treated macrophages and endotoxemic mice. Cynandione A- and PHA-543613-inhibited proinflammatory cytokine expression was completely blocked by the α7 nAChR antagonist methyllycaconitine and the IL-10 antibody. The stimulatory effect of cynandione A and PHA-543613 on IL-10 expression were suppressed by methyllycaconitine and knockdown of α7 nAChRs using siRNA/α7 nAChR. Cynandione A significantly stimulated STAT3 phosphorylation, which was attenuated by methyllycaconitine and the IL-10 neutralizing antibody. The STAT3 activation inhibitor NSC74859 also blocked cynandione A-inhibited proinflammatory cytokine expression. Taken together, our results, for the first time, demonstrate that cynandione A and PHA-543613 inhibit inflammation through macrophageal α7 nAChR activation and subsequent IL-10 expression.