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Geldanamycin Interferes with the 90-kDa Heat Shock Protein, Affecting Lipopolysaccharide-Mediated Interleukin-1 Expression and Apoptosis within Macrophages

Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan (H.-Y.H., S.-K.T., V.P.-H.L., W.-T.W., C.-H.C.); Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (H.-Y.H.); Department of Biochemistry and Molecular Biology, College of Medicine, and Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan (H.-L.W.); and Stephen M. Ross School of Business, University of Michigan, Ann Arbor, Michigan (J.H.)

We have demonstrated that lipopolysaccharide (LPS)-mediated reactive oxygen species (ROS) and signal transduction are involved in the regulation of interleukin-1 (IL-1) gene expression within macrophages. Because the 90-kDa heat shock protein (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 heterocomplex formation. In addition, Hsp90 is important for IL-1 protein translation, plays a minor role in IL-1 mRNA transcription, and is involved in nuclear factor-B activation and the phosphorylation and activation of p38, c-Jun NH₂-terminal kinase, and extracellular signal-regulated kinase; however, Hsp90 plays a more important role in LPS-stimulated p38 activation. In analyzing the function of Hsp90 regarding the cytotoxicity/viability of macrophages, we found that the combination of LPS and GA increases apoptosis, as evidenced by the increased caspase-3 activity and the proportion of nuclear/chromatin condensation. In contrast, N-acetyl-cysteine 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.

Address correspondence to: Dr. Hsien-Yeh Hsu, Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, 155 Li-Nong Street, Shih-Pai Taipei, Taiwan. E-mail: hyhsu{at}ym.edu.tw

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