Premium
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)
Author(s) -
Thangjam Gagan,
Snead Connie,
Black Stephen M,
Catravas John D
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1100.1
Subject(s) - nf κb , nfkb1 , iκbα , heat shock protein , endothelial activation , kinase , iκb kinase , hsp90 , microbiology and biotechnology , biology , chemistry , tumor necrosis factor alpha , signal transduction , inflammation , biochemistry , endocrinology , immunology , transcription factor , gene
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 pp60 c‐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 pp60 c‐src activation, over‐expression of an adenoviral dominant negative pp60 c‐src construct did not significantly alter the LPS‐induced decrease in IκB‐α expression and NFκB activation. Additionally, the GSK3β inhibitor, SB216763, failed to reverse the LPS‐mediated NFκB nuclear translocation and induction of Caveolin‐1 and ICAM‐1 mRNA. Our result suggests that although hsp90 inhibition prevents both NFκB activation and GSK3β and pp60 c‐src function and expression, LPS‐induced NFκB activation is not significantly dependent on GSK3β and pp60 c‐src in HLMVEC. The research project is supported by NIH grant HL093460.