ArticleAmerican journal of respiratory cell and molecular biology2008
Cytokines induce an early steroid resistance in airway smooth muscle cells: novel role of interferon regulatory factor-1.
Article in American journal of respiratory cell and molecular biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 93 citations in OpenAlex.
- A phase 2 multiple ascending dose study of the inhaled pan-JAK inhibitor nezulcitinib (TD-0903) in severe COVID-19.The European respiratory journal · 2021Trial
- Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics.BMC medical genomics · 2012Trial
- Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide.British journal of pharmacology · 2012Trial
- Flow cytometry analysis of glucocorticoid receptor expression and binding in steroid-sensitive and steroid-resistant patients with systemic lupus erythematosus.Arthritis research & therapy · 2009Trial
- Identifying Therapeutic Targets for Bronchial Asthma: Systematic Druggable Genome-Wide Mendelian Randomization.Health science reports · 2026Article
- Integrative Roles of Pro-Inflammatory Cytokines on Airway Smooth Muscle Structure and Function in Asthma.Immunological reviews · 2025Review
- Drugs Used in the Treatment of Viral Infections for the Prevention of Airway Remodeling in Asthma.Mediators of inflammation · 2025Review
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- Airway smooth muscle in contractility and remodeling of asthma: potential drug target mechanisms.Expert opinion on therapeutic targets · 2023Article
- Glucocorticoid Insensitivity in Asthma: The Unique Role for Airway Smooth Muscle Cells.International journal of molecular sciences · 2022Review
- Th1 cytokines synergize to change gene expression and promote corticosteroid insensitivity in pediatric airway smooth muscle.Respiratory research · 2022Article
- Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma.Frontiers in immunology · 2022Review
- Identification of Key Signaling Pathways and Genes in Eosinophilic Asthma and Neutrophilic Asthma by Weighted Gene Co-Expression Network Analysis.Frontiers in molecular biosciences · 2022Article
- Potential Role of Mast Cells in Regulating Corticosteroid Insensitivity in Severe Asthma.Advances in experimental medicine and biology · 2021Article
- Human Lung Mast Cells Impair Corticosteroid Responsiveness in Human Airway Smooth Muscle Cells.Frontiers in allergy · 2021Article
- Important lessons learned from studies on the pharmacology of glucocorticoids in human airway smooth muscle cells: Too much of a good thing may be a problem.Pharmacology & therapeutics · 2020Review
- Th1 cytokines TNF-α and IFN-γ promote corticosteroid resistance in developing human airway smooth muscle.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- CD38/cADPR Signaling Pathway in Airway Disease: Regulatory Mechanisms.Mediators of inflammation · 2018Review
- Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance.The Journal of biological chemistry · 2017Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
We have previously shown that long-term treatment of airway smooth muscle (ASM) cells with a combination of TNF-alpha and IFN-gamma impaired steroid anti-inflammatory action through the up-regulation of glucocorticoid receptor beta isoform (GRbeta) (Mol Pharmacol 2006;69:588-596). We here found that steroid actions could also be suppressed by short-term exposure of ASM cells to TNF-alpha and IFN-gamma (6 h) as shown by the abrogated glucocorticoid responsive element (GRE)-dependent gene transcription; surprisingly, neither GRalpha nuclear translocation nor GRbeta expression was affected by cytokine mixture. The earlier induction of CD38, a molecule recently involved in asthma, seen with TNF-alpha and IFN-gamma combination but not with cytokine alone, was also completely insensitive to steroid pretreatment. Chromatin-immunoprecipitation (IP) and siRNA strategies revealed not only increased binding of interferon regulatory factor 1 (IRF-1) transcription factor to CD38 promoter, but also its implication in regulating CD38 gene transcription. Interestingly, the capacity of fluticasone to completely inhibit TNF-alpha-induced IRF-1 expression, IRF-1 DNA binding, and transactivation activities was completely lost in cells exposed to TNF-alpha and IFN-gamma in combination. This early steroid dysfunction seen with cytokine combination could be reproduced by enhancing IRF-1 cellular levels using constitutively active IRF-1, which dose-dependently inhibited GRE-dependent gene transcription. Consistently, reducing IRF-1 cellular levels using siRNA approach significantly restored steroid transactivation activities. Collectively, our findings demonstrate for the first time that IRF-1 is a novel alternative GRbeta-independent mechanism mediating steroid dysfunction induced by pro-asthmatic cytokines, in part via the suppression of GRalpha activities.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.