Activation of AMPK suppresses S1P-induced airway smooth muscle cells proliferation and its potential mechanisms

• S1P promotes ASMCs proliferation in a S1PR 2/3 –dependent manner. • S1PR 2/3 /STAT3/PLK1/ID2 pathway mediates S1P-stimulated ASMCs proliferation. • Activation of AMPK by metformin suppresses S1P-evoked the proliferation of ASMCs. • The mechanisms underlying AMPK inhibition of ASMCs proliferation are associated with the suppression of S1P-induced STAT3 activation. 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 2/3 , and this further sequentially up-regulated polo-like kinase 1 (PLK1) and inhibitor of differentiation 2 (ID2) protein expression. Pretreatment of cells with S1PR 2 antagonist JTE-013, S1PR 3 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 2/3 /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.