Wang Cong, Feng Guo-Gang, Takagi Junko, Fujiwara Yoshihiro, Sano Tsuyoshi, Note Hideaki
Department of Gastroenterological Surgery, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute 480-1195, Aichi, Japan.
Department of Anesthesiology, Aichi Medical University School of Medicine, 1-1 Yazakokarimata, Nagakute 480-1195, Aichi, Japan.
Curr Issues Mol Biol. 2024 Oct 12;46(10):11336-11348. doi: 10.3390/cimb46100675.
Inflammation is a tightly regulated process involving immune receptor recognition, immune cell migration, inflammatory mediator secretion, and pathogen elimination, all essential for combating infection and restoring damaged tissue. However, excessive inflammatory responses drive various human diseases. The autonomic nervous system (ANS) is known to regulate inflammatory responses; however, the detailed mechanisms underlying this regulation remain incompletely understood. Herein, we aimed to study the anti-inflammatory effects and mechanism of action of the ANS in RAW264.7 cells. Quantitative PCR and immunoblotting assays were used to assess lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) expression. The anti-inflammatory effects of catecholamines (adrenaline, noradrenaline, and dopamine) and acetylcholine were examined in LPS-treated cells to identify the receptors involved. Catecholamines inhibited LPS-induced TNFα expression by activating the β2 adrenergic receptor (β2-AR). β2-AR activation in turn downregulated the expression of Toll-like receptor 4 (TLR4) by stimulating protein kinase A (PKA) phosphorylation, resulting in the suppression of TNFα levels. Collectively, our findings reveal a novel mechanism underlying the inhibitory effect of catecholamines on LPS-induced inflammatory responses, whereby β2-AR activation and PKA phosphorylation downregulate TLR4 expression in macrophages. These findings could provide valuable insights for the treatment of inflammatory diseases and anti-inflammatory drug development.
炎症是一个受到严格调控的过程，涉及免疫受体识别、免疫细胞迁移、炎症介质分泌和病原体清除，所有这些对于对抗感染和修复受损组织都是必不可少的。然而，过度的炎症反应会引发各种人类疾病。已知自主神经系统（ANS）可调节炎症反应；然而，这种调节的详细机制仍未完全了解。在此，我们旨在研究ANS在RAW264.7细胞中的抗炎作用及其作用机制。采用定量PCR和免疫印迹分析来评估脂多糖（LPS）诱导的肿瘤坏死因子α（TNFα）的表达。在LPS处理的细胞中检测儿茶酚胺（肾上腺素、去甲肾上腺素和多巴胺）和乙酰胆碱的抗炎作用，以确定相关受体。儿茶酚胺通过激活β2肾上腺素能受体（β2-AR）抑制LPS诱导的TNFα表达。β2-AR激活进而通过刺激蛋白激酶A（PKA）磷酸化来下调Toll样受体4（TLR4）的表达，从而导致TNFα水平的抑制。总的来说，我们的研究结果揭示了儿茶酚胺对LPS诱导的炎症反应产生抑制作用的一种新机制，即β2-AR激活和PKA磷酸化下调巨噬细胞中TLR4的表达。这些发现可为炎症性疾病的治疗和抗炎药物的开发提供有价值的见解。
