Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Pulmonary and Critical Care Medicine, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Mol Immunol. 2020 Dec;128:106-115. doi: 10.1016/j.molimm.2020.09.020. Epub 2020 Oct 22.
The aims of the present study were to investigate the signaling mechanisms for sphingosine-1-phosphate (S1P)-induced airway smooth muscle cells (ASMCs) proliferation and to explore the effect of activation of adenosine monophosphate-activated protein kinase (AMPK) on S1P-induced ASMCs proliferation and its underlying mechanisms. S1P phosphorylated signal transducer and activator of transcription 3 (STAT3) through binding to S1PR, and this further sequentially up-regulated polo-like kinase 1 (PLK1) and inhibitor of differentiation 2 (ID2) protein expression. Pretreatment of cells with S1PR antagonist JTE-013, S1PR antagonist CAY-10444, knockdown of STAT3, PLK1 and ID2 attenuated S1P-triggered ASMCs proliferation. In addition, activation of AMPK by metformin inhibited S1P-induced ASMCs proliferation by suppressing STAT3 phosphorylation and therefore suppression of PLK1 and ID2 protein expression. Our study suggests that S1P promotes ASMCs proliferation by stimulating S1PR/STAT3/PLK1/ID2 axis, and activation of AMPK suppresses ASMCs proliferation by targeting on STAT3 signaling pathway. Activation of AMPK might benefit asthma by inhibiting airway remodeling.
本研究旨在探讨鞘氨醇-1-磷酸（S1P）诱导的气道平滑肌细胞（ASMCs）增殖的信号转导机制，并探讨激活单磷酸腺苷激活的蛋白激酶（AMPK）对 S1P 诱导的 ASMCs 增殖及其潜在机制的影响。S1P 通过与 S1PR 结合磷酸化信号转导和转录激活因子 3（STAT3），进而依次上调丝氨酸苏氨酸激酶（PLK1）和分化抑制因子 2（ID2）蛋白表达。用 S1PR 拮抗剂 JTE-013、S1PR 拮抗剂 CAY-10444 预处理细胞，或敲低 STAT3、PLK1 和 ID2，均可减弱 S1P 引发的 ASMCs 增殖。此外，二甲双胍激活 AMPK 通过抑制 STAT3 磷酸化从而抑制 PLK1 和 ID2 蛋白表达，抑制 S1P 诱导的 ASMCs 增殖。本研究表明，S1P 通过刺激 S1PR/STAT3/PLK1/ID2 轴促进 ASMCs 增殖，而激活 AMPK 通过靶向 STAT3 信号通路抑制 ASMCs 增殖。AMPK 的激活可能通过抑制气道重塑有益于哮喘。
