HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

Shimp, Samuel K.; Parson, Carl; Regna, Nicole L.; Thomas, Alicia; Chafin, Cristen B.; Reilly, Christopher M.; Rylander, Marissa Nichole

doi:10.1007/s00011-012-0442-x

Cited by 50 publications

(41 citation statements)

References 67 publications

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“…17-Dimethylaminoethylamino-17-demethoxygeldanamycin reduces inflammation in lupus (39), blocks the NF-B inflammatory cascade in immune stimulated macrophages (40) and substantially reduces necrosisinduced cytokine production and permeability increases in a model of endotoxin-induced uveitis (34). Moreover, the synthetic Hsp90 inhibitor EC144 appears to be efficacious in mouse models of endotoxin shock and arthritis (51).…”

Section: Discussionmentioning

confidence: 99%

LPS induces pp60^c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung

Barabutis

Handa

Dimitropoulou

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Heat shock protein 90 (Hsp90) inhibitors were initially developed as anticancer agents; however, it is becoming increasing clear that they also possess potent anti-inflammatory properties. Posttranslational modifications of Hsp90 have been reported in tumors and have been hypothesized to affect client protein- and inhibitor-binding activities. In the present study we investigated the posttranslational modification of Hsp90 in inflammation. LPS, a prototypical inflammatory agent, induced concentration- and time-dependent tyrosine (Y) phosphorylation of Hsp90α and Hsp90β in bovine pulmonary arterial and human lung microvascular endothelial cells (HLMVEC). Mass spectrometry identified Y309 as a major site of Y phosphorylation on Hsp90α (Y300 of Hsp90β). LPS-induced Hsp90 phosphorylation was prevented by the Hsp90 inhibitor 17-allyl-amino-demethoxy-geldanamycin (17-AAG) in vitro as well as in lungs from LPS-treated mice, in vivo. Furthermore, 17-AAG prevented LPS-induced pp60src activation. LPS-induced Hsp90 phosphorylation was also prevented by the pp60src inhibitor PP2. Additionally, Hsp90 phosphorylation was induced by infecting cells with a constitutively active pp60src adenovirus, whereas either a dominant-negative pp60src adenovirus or reduced expression of pp60src by a specific siRNA prevented the LPS-induced Y phosphorylation of Hsp90. Transfection of HLMVEC with the nonphosphorylatable Hsp90β Y300F mutant prevented LPS-induced Hsp90β tyrosine phosphorylation but not pp60src activation. Furthermore, the Hsp90β Y300F mutant showed a reduced ability to bind the Hsp90 client proteins eNOS and pp60src and HLMVEC transfected with the mutant exhibited reduced LPS-induced barrier dysfunction. We conclude that inflammatory stimuli cause posttranslational modifications of Hsp90 that are Hsp90-inhibitor sensitive and may be important to the proinflammatory actions of Hsp90.

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Section: Discussionmentioning

confidence: 99%

LPS induces pp60^c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung

Barabutis

Handa

Dimitropoulou

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…HSP90, a highly conserved and abundant 90 kDa protein, is involved in chaperoning the structures of over 200 client proteins, many of which are involved in growth control as well as mammary tumor cell proliferation [59]. Based on scientific reports, HSP90 may regulate inflammatory events through the modulation of various cytokines and cell signaling pathways [60,61,62]. The efficacy of various HSP90 inhibitors in the treatment of several oncologic diseases, including breast cancer, is currently underway [63,64,65].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways

2017

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Pomegranate (Punica granatum L.), a nutrient-rich unique fruit, has been used for centuries for the prevention and treatment of various inflammation-driven diseases. Based on our previous study, a characterized pomegranate emulsion (PE) exhibited a striking inhibition of dimethylbenz(a)anthracene (DMBA)-initiated rat mammary tumorigenesis via antiproliferative and apoptosis-inducing mechanisms. The objective of the present work is to investigate the anti-inflammatory mechanism of action of PE during DMBA rat mammary carcinogenesis by evaluating the expression of cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-κB (NF-κB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). Mammary tumor samples were harvested from our previous chemopreventive study in which PE (0.2–5.0 g/kg) was found to reduce mammary tumorigenesis in a dose-dependent manner. The expressions of COX-2, HSP90, NF-κB, inhibitory κBα (IκBα) and Nrf2 were detected by immunohistochemical techniques. PE decreased the expression of COX-2 and HSP90, prevented the degradation of IκBα, hindered the translocation of NF-κB from cytosol to nucleus and increased the expression and nuclear translocation of Nrf2 during DMBA-induced mammary tumorigenesis. These findings, together with our previous results, indicate that PE-mediated prevention of DMBA-evoked mammary carcinogenesis may involve anti-inflammatory mechanisms through concurrent but differential regulation of two interrelated molecular pathways, namely NF-κB and Nrf2 signaling.

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“…Moreover, previous data indicate that HSP90-targeted agents may be helpful for the treatment of inflammatory disease, and that an HSP90 inhibitor can affect multiple signaling processes associated with inflammation (27). Furthermore, inhibition of HSP90 is able to reduce innate immunity responses and diminishes proinflammatory mediator production in immune-stimulated macrophages (28,29). In addition, analysis of inflammatory mediators in crevicular fluid can be used to distinguish peri-implantitis from normal tissue (30).…”

Section: Discussionmentioning

confidence: 99%

Identification of key genes and pathways for peri-implantitis through the analysis of gene expression data

Zhang

Huang

et al. 2017

Experimental and Therapeutic Medicine

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The present study attempted to identify potential key genes and pathways of peri-implantitis, and to investigate the possible mechanisms associated with it. An array data of GSE57631 was downloaded, including six samples of peri-implantitis tissue and two samples of normal tissue from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in the peri-implantitis samples compared with normal ones were analyzed with the limma package. Moreover, Gene Ontology annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses for DEGs were performed by DAVID. A protein-protein interaction (PPI) network was established using Cytoscape software, and significant modules were analyzed using Molecular Complex Detection. A total of 819 DEGs (759 upregulated and 60 downregulated) were identified in the peri-implantitis samples compared with normal ones. Moreover, the PPI network was constructed with 413 nodes and 1,114 protein pairs. Heat shock protein HSP90AA1 (90 kDa α, member 1), a hub node with higher node degrees in module 4, was significantly enriched in antigen processing, in the presentation pathway and nucleotide-binding oligomerization domain (NOD)-like receptor-signaling pathway. In addition, nuclear factor-κ-B1 (NFKB1) was enriched in the NOD-like receptor-signaling pathway in KEGG pathway enrichment analysis for upregulated genes. The proteasome is the most significant pathway in module 1 with the highest P-value. Therefore, the results of the present study suggested that HSP90AA1 and NFKB1 may be potential key genes, and the NOD-like receptor signaling pathway and proteasome may be potential pathways associated with peri-implantitis development.

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HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

Abstract: Our studies show that the immune-mediated NF-κB inflammatory cascade is blocked by the HSP90 inhibitor 17-DMAG. Due to the broad interaction of HSP90 with many pro-inflammatory kinase cascades, inhibition of HSP90 may provide a novel approach to reducing chronic inflammation.

Cited by 50 publications

References 67 publications

LPS induces pp60^c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung

LPS induces pp60^c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung

Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways

Identification of key genes and pathways for peri-implantitis through the analysis of gene expression data

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HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

Abstract: Our studies show that the immune-mediated NF-κB inflammatory cascade is blocked by the HSP90 inhibitor 17-DMAG. Due to the broad interaction of HSP90 with many pro-inflammatory kinase cascades, inhibition of HSP90 may provide a novel approach to reducing chronic inflammation.

Cited by 50 publications

References 67 publications

LPS induces pp60c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung

LPS induces pp60c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung

Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-κB and Nrf2 Signaling Pathways

Identification of key genes and pathways for peri-implantitis through the analysis of gene expression data

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LPS induces pp60^c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung

LPS induces pp60^c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung