Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance
Open accessAbstract
Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNA-destabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-κB (NF-κB), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid.
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Increased proinflammatory milieu acts to further upregulate HPA axis in an attempt to restore homeostasis, at the cost of dysregulated immune response.
“This results in increased proinflammatory milieu that acts to further upregulate HPA axis in an attempt to restore homeostasis, however, at the cost of dysregulated immune response (55).”
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- Authors
- Newton, R., Shah, S., Altonsy, M. O., & Gerber, A. N.
- Affiliations
- University of Calgary (CA)
- National Jewish Health (US)
- Corresponding author
- Newton, Robert
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 292
- Issue
- 17
- Pages
- 7163-7172
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5409484
- OpenAlex
- W2593975322
- Cited by
- 91
- References
- 99
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 10 · 2023: 14 · 2022: 9 · 2021: 16 · 2020: 16 · 2019: 7 · 2018: 5 · 2017: 3
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP 125918)
- Alberta Innovates - Health Solutions (Senior Scholar)
- National Heart, Lung, and Blood Institute (R01 HL-109557)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- glucocorticoid receptor, glucocorticoid resistance, inflammatory gene expression, negative feedback regulation, feedforward control, cytokine signaling, MKP-1, A20, ZFP36, NF-κB, MAPK signaling, IRF1, CXCL10, transcriptional repression
- MeSH terms
- A549 Cells, Tumor Necrosis Factor alpha-Induced Protein 3, Animals, Gene Expression Regulation, Glucocorticoids, Humans, Inflammation, Receptors, Glucocorticoid, RNA, Messenger, Signal Transduction, Gene Expression Regulation, Neoplastic, Cytokines, NF-kappa B, MAP Kinase Signaling System, Feedback, Physiological, Interferon Regulatory Factor-1, Mice, Tristetraprolin, Transcription Factor RelA, Chemokine CXCL10, Dual Specificity Phosphatase 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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