Received for publication March 8, 2006.
Revised July 3, 2006.
Accepted for publication July 6, 2006.

Geldanamycin interferes with Hsp90, affecting LPS-mediated IL-1 expression and apoptosis within macrophages

Abstract

We have demonstrated that lipopolysaccharide (LPS)-mediated reactive oxygen species (ROS) and signal transduction are involved in the regulation of interleukin-1 beta (IL-1) gene expression within macrophages. Since heat shock protein 90 (Hsp90) plays an important role in the LPS mediation of macrophage activation, using Hsp90 inhibitor geldanamycin A (GA), we analyzed the mechanism of Hsp90 upon LPS-transduced signaling in the regulation of IL-1 expression, and determined the function of Hsp90 regarding the viability of human primary macrophages and murine macrophages cell line. In essence, GA decreased LPS-induced Hsp90/pp60Src hetero-complex formation. In addition, Hsp90 is important for IL-1 protein translation, plays a minor role in IL-1 mRNA transcription, and is involved in NF-B activation, as well as the phosphorylation and activation of p38, JNK and ERK; however, Hsp90 plays a more important role in LPS-stimulated p38 activation. In analysing the function of Hsp90 as regards the cytotoxicity/viability of macrophages, we found that the combination of LPS and GA increases apoptosis, evidenced by the increased caspase-3 activity and the proportion of nuclear/chromatin condensation. In contrast, NAC dramatically blocked GA/LPS-induced ROS production, simultaneously decreasing caspase-3 activity and the presence of apoptotic nuclei. We concluded that Hsp90 plays an indispensable role in the process of LPS-induced IL-1 secretion. Furthermore, we established the mechanism of GA interference with Hsp90 function for LPS-stimulated macrophages, resulting in increased ROS production and caspase-3 activation, and consequently leading to synergistic enhancement of macrophage apoptosis.

Key words: Interleukins, MAP Kinase, P38 MAP Kinase, NFkappaB, Apoptosis, Oxidative stress

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