Hsp90 Inhibition Attenuates The Lps-Mediated Phosphorylation Of Creb And Stat3 In Human Lung Microvascular Endothelial Cells

We have previously shown that Hsp90 inhibitors protect and restore bacterial lipopolysaccharide (LPS)‐mediated endothelial barrier dysfunction. However, the underlying mechanisms for this action of Hsp90 inhibitors remain unclear. CREB and STAT3 are important pro‐inflammatory transcription factors. Our aim here is to delineate the mechanisms of LPS‐mediated phosphorylation and activation of CREB and STAT3 and its regulation by the Hsp90 inhibitor 17AAG in human lung microvascular endothelial cells (HLMVEC). Pre‐treatment of HLMVEC with 17AAG attenuated phosphorylation of both CREB and STAT3. Furthermore, 17AAG attenuated expression of CREB target genes, GADD45B and NR4A2, and STAT3 target genes, cMyc and IL6, suggesting that 17AAG decreases LPS‐mediated transcriptional activation of both CREB and STAT3. Pre‐treatment with either the p38 MAPK inhibitor (SB203580) or the PKA/MSK1 inhibitor (H89) completely abolished the LPS‐mediated CREB and STAT3 phosphorylation. Furthermore, treatment with Src family kinase (SFK) inhibitors PP1 and PP2 exhibited partial attenuation of CREB and STAT3 phosphorylation. These data suggest that the Hsp90 inhibitor, 17AAG, attenuates LPS‐mediated phosphorylation and activation of both CREB and STAT3 via the p38 MAPK and SFK pathways. (Supported by HL093460 and HL101902)