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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Inhibitory effects of heat shock protein 90 blockade on proinflammatory human Th1 and Th17 cell subpopulations
Stefan Tukaj, Detlef Zillikens, Michael Kasperkiewicz1
1Department of Dermatology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. Michael.Kasperkiewicz@uk-sh.de.
Background:
Heat shock protein 90 (Hsp90), a chaperone that regulates activity of many client proteins responsible for cellular growth, differentiation, and apoptosis, has been proposed as an important clinical and preclinical therapeutic target in a number of malignancies and autoimmune diseases, respectively. In this study, we evaluated the effects of pharmacological Hsp90 inhibition on human proinflammatory T cell responses.
Findings:
Using anti-CD3 antibody-stimulated human peripheral blood mononuclear cell cultures, we observed that Hsp90 inhibition by non-toxic concentrations of the geldanamycin derivative 17-DMAG significantly blocked T cell proliferation, reduced IFN-γ and IL-17 expression on CD4+ T lymphocytes, and arrested secretion of proinflammatory IFN-γ, TNF-α, and IL-17, cytokines characteristic of Th1 and Th17 cells, respectively. These effects were associated with inhibition of NF-kB activity, upregulation of Hsp70 protein expression, and disruption of T cell-specific nonreceptor tyrosine kinase Lck activation.
Conclusions:
Our results further support the potential use of Hsp90 inhibitors in patients with autoimmune diseases where uncontrolled Th1 or Th17 activation frequently occurs.
Insights
Pharmacological inhibition of Heat Shock Protein 90 (Hsp90) blocks T cell proliferation and reduces key inflammatory cytokines. This suggests Hsp90 inhibitors may treat autoimmune diseases driven by T cell activation.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Heat shock protein 90 (Hsp90) is a crucial chaperone protein involved in cellular growth, differentiation, and apoptosis.
- Hsp90 is a validated therapeutic target for various cancers and autoimmune diseases.
- Understanding Hsp90's role in T cell responses is critical for developing targeted therapies.
Purpose of the Study:
- To investigate the effects of pharmacological Hsp90 inhibition on human proinflammatory T cell responses.
- To determine the impact of Hsp90 inhibition on T cell proliferation and cytokine production.
Main Methods:
- Human peripheral blood mononuclear cells were stimulated with anti-CD3 antibody.
- Non-toxic concentrations of 17-DMAG, a geldanamycin derivative, were used to inhibit Hsp90.
- Flow cytometry and cytokine assays were employed to analyze T cell responses.
Main Results:
- Hsp90 inhibition significantly blocked T cell proliferation.
- Reduced expression of IFN-γ and IL-17 on CD4+ T lymphocytes was observed.
- Secretion of proinflammatory cytokines IFN-γ, TNF-α, and IL-17 was arrested.
- Inhibition of NF-kB activity, upregulation of Hsp70, and disrupted Lck activation were associated findings.
Conclusions:
- Hsp90 inhibition effectively suppresses key pathways driving Th1 and Th17 cell activation.
- These findings support the potential therapeutic application of Hsp90 inhibitors in autoimmune diseases characterized by uncontrolled T cell responses.
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