The heat shock protein 90 inhibitor 17‐(Allylamino)‐17‐demethoxygeldanamycin (17‐AAG) abrogates the LPS‐mediated NFκB activation in human lung microvascular endothelial cells (HLMVEC)

TL;DRAbstract

Nuclear factor-kappa B (NFκB) is responsible –at least in part- for the dysregulation of endothelial integrity upon exposure to gram-negative bacterial lipopolysaccharide (LPS). Several upstream kinases facilitate NFκB activation. Here we address the role of hsp90 client proteins Glycogen Synthase Kinase 3β (GSK3β) and pp60c-src in LPS-mediated NFκB activation. Exposure of HLMVEC to LPS decreased cytosolic IκB-α expression, increased nuclear translocation of the NFκB subunits, p65/Rel-A and p50 (indices of NFκB activation) and increased the NFκB-dependent mRNA of Caveolin-1 and ICAM-1. Pretreatment of HLMVEC with 17-AAG restored IκB-α expression, prevented NFκB subunit nuclear translocation and blocked Caveolin-1 and ICAM-1 mRNA induction by LPS. Even though 17-AAG prevented pp60c-src activation, over-expression of an adenoviral dominant negative pp60c-src construct did not significantly alter the LPS-induced decrease in IκB-α expression and NFκB activation. Additionally, the GSK3β inh

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