S1P promotes inflammation-induced tube formation by HLECs via the S1PR1/NF-κB pathway

Inflammation-induced lymphangiogenesis is a widely accepted concept. However, most of the inflammatory factors and their related mechanisms have not been clarified. It has been reported that sphingosine-1-phosphate (S1P) is not only closely related to the chronic inflammatory process but also affects angiogenesis. Therefore, we investigated the inflammatory effects of S1P on human lymphatic endothelial cells (HLECs). Our results showed that S1P promotes tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) secretion in HLECs. We also confirmed that S1P-stimulated TNF-α and IL-1β secretion is mediated through S1P receptor 1 (S1PR1). Using TNF-α siRNA and IL-1β siRNA, we found that TNF-α and IL-1β play essential roles in S1P-induced HLEC proliferation, migration, and tube formation. S1P induces phosphorylation of NF-κB p65 and activation of NF-κB nuclear translocation. A S1PR1 antagonist (W146) and NF-κB inhibitor (BAY11-7082) inhibited S1P-induced TNF-α and IL-1β secretion and prevented NF-κB nuclear translocation. Taken together, the results demonstrated for the first time that S1P promotes the secretion of TNF-α and IL-1β in HLECs via S1PR1-mediated NF-κB signaling pathways, thus affecting lymphangiogenesis. The study provides a new strategy for finding treatments for lymphangiogenesis-related diseases.