HSP90 Inhibition by 17-DMAG Reduces Inflammation in J774 Macrophages Through Suppression of Akt and Nuclear Factor-κB Pathways

Overview

Journal Inflamm Res

Specialties Allergy & Immunology
Pathology

Date 2012 Feb 14

PMID 22327510

Citations 33

Authors

Samuel K Shimp 3rd

Carl D Parson

Nicole L Regna

Alicia N Thomas

Cristen B Chafin

Christopher M Reilly

M Nichole Rylander

Affiliations

Soon will be listed here.

Abstract

Objective: This study was designed to determine whether inhibition of heat shock protein 90 (HSP90) reduces pro-inflammatory mediator production by decreasing the nuclear factor (NF)-κB and Akt signaling pathways in immune-stimulated macrophages.

Methods: J774A.1 murine macrophages were treated with the HSP90 inhibitor 17-DMAG (0.01, 0.1 or 1 μM) prior to immune stimulation with lipopolysaccharide and interferon-γ. Expression of Akt, inhibitor of κB kinase (IKK), and heat shock proteins were measured in whole cell lysates by Western blotting. Phosphorylated Akt and inhibitor of κB (IκB) were measured in whole cell lysates by ELISA. Cell supernatants were analyzed for interleukin (IL)-6, tumor necrosis factor (TNF)-α and nitric oxide (NO). Translocation of NF-κB and heat shock factor (HSF)-1 was assessed by immunofluorescence.

Results: Treating cells with 17-DMAG reduced expression of Akt and IKK in immune-stimulated cells. 17-DMAG reduced nuclear translocation of NF-κB and reduced immune-stimulated production of IL-6, TNF-α and NO, but did not decrease inducible nitric oxide synthase expression.

Conclusions: 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.

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