Unfractionated heparin attenuates LPS-induced IL-8 secretion via PI3K/Akt/NF-κB signaling pathway in human endothelial cells

Unfractionated heparin (UFH) is largely used as anti-thrombotic drug. While UFH has been shown to suppress lipopolysaccharide (LPS)-induced nuclear factor-kappa B (NF-kappa B) activation, intracellular upstream events that cause NF-kappa B down-regulation in response to UFH remain unclear. Thus, we investigated the involvement of phosphoinositide-3-OH kinase (PI3K)/Akt in the inhibition of LPS-activated NF-kappa B pathway by UFH in human pulmonary microvascular endothelial cells (HPMECs). Pretreatment with UFH (0.1-1 U/ml) significantly inhibited LPS (10 mu g/ml)-stimulated interleukin (IL)-6 and IL-8 production in HPMECs. LPS activated Akt and NF-kappa B, whereas UFH suppresses LPS-induced Akt phosphorylation and NF-kappa B nuclear translocation, which were required for IL-6 and IL-8 gene transcription. Inhibition studies by using wortmannin abrogated NF-kappa B-mediated IL-6 and IL-8 expression, suggesting the requirement of PI31(/Akt pathway. Our data provided the first evidence that UFH might repress LPS-activated PI3K/Akt pathway, leading to inhibitory effect of NF-kappa B activation with diminished IL-6 and IL-8 expression in HPMECs. (C) 2014 Elsevier GmbH. All rights reserved.