HSP90 inhibitor geldanamycin reverts IL-13– and IL-17–induced airway goblet cell metaplasia

Pezzulo, Alejandro A.; Tudas, R.A.; Stewart, Carley G.; Buonfiglio, Luis G. Vargas; Lindsay, Brian D.; Taft, Peter J.; Gansemer, Nicholas D.; Zabner, Joseph

doi:10.1172/jci123524

Cited by 47 publications

(57 citation statements)

References 160 publications

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“…IL-13 treatment induced an increase in MUC5AC staining, as we expected. Consistent with our prior findings, treatment of HPS90i with IL-13 blocked this significant increase in MUC5AC (13). Moreover, exposure to IL-13 induced phosphorylation of p100 S869.…”

Section: Hsp90 Inhibition Blocks Il-13-induced Phosphorylation Of P10supporting

confidence: 92%

“…We have previously shown that HSP90 inhibition blocks and partially reverts IL-13-induced goblet cell metaplasia in primary human airway epithelia in vitro (13). HSP90 is known to interact with many client proteins.…”

Section: Hsp90 Inhibition Modulates Phosphorylation Of Several Proteimentioning

confidence: 99%

“…With continued IL-13 treatment, an HSP90 inhibitor (HSP90i, 25µM geldanamycin), was then added for 1, 2, 7, or 14 days. This dosage of IL-13 and geldanamycin was used in all experiments and was previously determined (13). To measure modulation of protein phosphorylation, we performed a Phospho-Explorer antibody array and evaluated the effect of HSP90 inhibition on the phosphorylation of numerous proteins in IL-13-exposed airway epithelial cells.…”

Section: Hsp90 Inhibition Modulates Phosphorylation Of Several Proteimentioning

confidence: 99%

“…Heat shock protein 90 (HSP90) is important for both IL-13-and IL-17-induced goblet cell metaplasia. We previously showed that HSP90 inhibition blocks and reverts IL-13-and IL-17-induced goblet cell metaplasia in human airway epithelia cells in vitro and in mice in vivo (13). HSP90 is a chaperone protein required in the proper folding and stabilization of hundreds of client proteins.…”

Section: Introductionmentioning

confidence: 99%

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HSP90 inhibition modulates NFκB signaling in airway goblet cell metaplasia

Tudas

Gannon

Thurman

et al. 2020

Preprint

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Goblet cell metaplasia and mucus hyper-production are key features of chronic muco-obstructive lung diseases such as asthma, chronic bronchitis, and cystic fibrosis. Various mechanisms lead to goblet cell metaplasia in the airways; the driving mechanism for goblet cell metaplasia in a specific patient may be unknown. We recently found that heat shock protein 90 (HSP90) is important for both IL-13-and IL-17induced airway goblet cell metaplasia. HSP90 interacts with multiple clients that are important in goblet cell metaplasia including Akt, Jak/STAT, IRS, Notch, and various kinases involved in NFκB signaling.Here, we used a targeted phospho-proteomic approach to identify candidate HSP90 clients modulated by the HSP90-inhibitor geldanamycin. NFκB family members were enriched amongst the top candidate targets of HSP90 inhibition in IL-13 an organotypic model of human airway epithelia. We hypothesized that HSP90 inhibition modulated goblet cell metaplasia by interfering with NFκB signaling. We used transcription factor activation, nuclear translocation, and phospho-specific immunofluorescence assays to investigate how IL-13 exposure and HSP90 inhibition modulated NFκB. We found that HSP90 inhibition prevented goblet cell metaplasia by non-canonically blocking NFκB p100/p52 function in human airway epithelia. NFκB modulation via its interaction with HSP90 is a pharmaceutically feasible therapeutic target for goblet cell metaplasia; this approach may enable treatment of patients with chronic mucoinflammatory lung diseases with both known or unidentified disease-driving mechanisms.

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Section: Hsp90 Inhibition Blocks Il-13-induced Phosphorylation Of P10supporting

confidence: 92%

Section: Hsp90 Inhibition Modulates Phosphorylation Of Several Proteimentioning

confidence: 99%

Section: Hsp90 Inhibition Modulates Phosphorylation Of Several Proteimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HSP90 inhibition modulates NFκB signaling in airway goblet cell metaplasia

Tudas

Gannon

Thurman

et al. 2020

Preprint

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“…IL-17 is activated after binding to the receptors of target cells and ultimately promotes the release of large amounts of in ammatory cytokines from target cells, which is one of many causes of neuronal death in individuals with depression [47]. In addition, some pathological phenomena induced by IL-17 can be reversed by inhibiting the activity of Hsp90 family proteins [48].…”

Section: Discussionmentioning

confidence: 99%

A Study of Icariin Modulating Hippocampal Neurogenesis in Depression Based on Quantitative CSF Proteomics

Zeng

Wang

et al. 2020

Preprint

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BackgroundHippocampal neurogenesis dysfunction is one of the main pathogenesis of depression. Icariin (ICA) has significant anti-depression and anti-hippocampal damage effects but could not effectively cross the blood-brain-barrier and accumulate in brain. Based on the proteomics of cerebrospinal fluid (CSF), this study aimed to explore the mechanism of ICA against hippocampal neurogenesis dysfunction in depression.MethodsIn vivo, rats were exposed to 6-week CUMS and treated by ICA to observe the effects of ICA on depressive symptoms, cognitive functions, neurogenesis and number of neurons in DG. Tandem mass tag (TMT) proteomics were used to screen the differentially expressed proteins (DEPs) in CSF co-regulated by CUMS and ICA. Parallel reaction monitoring (PRM) was used to validate 10 DEPs that were related to cell proliferation and survival. In vitro, CSF was conducted on primary hippocampal neural stem cells (NSCs) to observe the proliferation and differentiation under high-corticosterone (CORT) concentration.ResultsIt was shown that ICA could alleviate depressive symptoms, learning-memory dysfunction, neurogenesis dysfunction and neuronal loss in DG of depression rats and ICA-CSF could effectively repair the CORT-induced damage. A total of 52 DEPs co-regulated by CUMS and ICA in CSF were screened and mainly involved in ribosome pathway, PI3K-Akt pathway and IL-17 pathway. Rps4x, Rps12, Rps14, Rps19, Hsp90b1, Hsp90aa1 and HtrA1 were validated by PRM.ConclusionsThese findings indicate that to regulate the expression of proteins in CSF may be involved in the effects of ICA against hippocampal neurogenesis dysfunction in depression.

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Reduced miR‐513a‐5p expression in COPD may regulate airway mucous cell hyperplasia through TFR1‐dependent signaling

Zhou,

Du,

et al. 2023

The Kaohsiung J of Med Scie

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Airway mucous cell metaplasia and mucous hypersecretion is one of the key characteristic pathophysiological status of chronic obstructive pulmonary disease (COPD). micro(mi)RNAs are acknowledged as non‐encoding RNA molecules playing important roles in gene expression regulation. In this study, we searched the Gene Expression Omnibus (GEO) database for the differentially expressed miRNAs between COPD and non‐COPD controls with bioinformatics analysis. Finally, we focused on miR‐513a‐5p and investigated the potential mechanism by which miR‐513a‐5p regulates airway mucous hypersecretion and goblet cell metaplasia. A dual‐luciferase reporter assay was then showing that miR‐513a‐5p targeted the 3′‐UTR of TFR1 and inhibited its expression in vitro. In vivo transfection demonstrated that TFR1 downregulation partially blocked MUC5AC hypersecretion and goblet cell hyperplasia in COPD model rats. In vitro study, CSE increased the intracellular expression and secretion of MUC5AC by BEAS‐2B branchial epithelial cells in the BEAS‐2B cell and THP‐1 cell coculture system. Coculture with either miR‐513a‐5p mimic‐pretreated or TFR1‐deficient THP‐1 cells attenuated intracellular MUC5AC expression in BEAS‐2B cells exposed to CSE. ELISA demonstrated that transfection of TFR1 siRNA or pretreatment with miR‐513a‐5p mimic reduced the secretion of inflammatory factors that are responsible for airway goblet cell hyperplasia, such as IL‐1β, IL‐13, and IL‐17, by THP‐1 cells after CSE stimulation. Our findings supported that miR‐513a‐5p/TFR1 signaling axis might activate macrophages as well as promote airway inflammation and airway mucous cell hyperplasia in COPD.

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HSP90 inhibitor geldanamycin reverts IL-13– and IL-17–induced airway goblet cell metaplasia

Abstract: experiments. AP and CS were responsible for the high-throughput sample preparation and data analysis.

Cited by 47 publications

References 160 publications

HSP90 inhibition modulates NFκB signaling in airway goblet cell metaplasia

HSP90 inhibition modulates NFκB signaling in airway goblet cell metaplasia

A Study of Icariin Modulating Hippocampal Neurogenesis in Depression Based on Quantitative CSF Proteomics

Reduced miR‐513a‐5p expression in COPD may regulate airway mucous cell hyperplasia through TFR1‐dependent signaling

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