Infection/InflammationThe p38/mitogen-activated protein kinase pathway is implicated in lipopolysaccharide-induced microtubule depolymerization via up-regulation of microtubule-associated protein 4 phosphorylation in human vascular endothelium

BackgroundMicrotubules (MTs) play an important role in lipopolysaccharide (LPS)-induced overexpression of inflammatory cytokines and vascular barrier dysfunction; however, the mechanisms behind MT dynamics changes in the vascular endothelium under septic conditions are still not well understood.MethodsHuman umbilical vein endothelial cells (HUVECs) stimulated with LPS were pretreated with or without the specific p38/mitogen-activated protein kinase (MAPK) inhibitor, SB203580. p38/MAPK cascade-induced signaling events and proteins expression were investigated by Western blotting assay. The interaction between p38/MAPK and microtubule-associated protein 4 (MAP4) was examined by immunoprecipitation. Furthermore, the effects of agonists on LPS-induced MT disruption and alteration of acetylated alpha-tubulin (Acet-tubulin) were analyzed by double-immunofluorescent assay and Western blotting analysis.ResultsIn the present study, our results indicated that LPS induced MT depolymerization, but the effects of LPS could be reversed in endothelial cells pretreated with taxol. Furthermore, phosphor-p38 and MAP4 interacted to form a complex after exposure to LPS. LPS-induced MAP4 phosphorylation was greatly suppressed by SB203580, suggesting that activation of p38/MAPK signaling affected MAP4 phosphorylation linked to MT acetylation after stimulation with LPS.ConclusionThe present study demonstrated that the p38/MAPK signaling pathway might disrupt MT dynamics via phosphorylation of MAP4 in vascular endothelial cells challenged by LPS. Our findings provide novel insights into the pathogenic mechanism of MT disassembly and consider new targets for therapeutic intervention under sepsis or septic shock conditions.