Mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors sensitize reduced glucocorticoid response mediated by TNFα in human epidermal keratinocytes (HaCaT)
Abstract
Glucocorticoids (GCs) are essential drugs administered topically or systematically for the treatment of autoimmune skin diseases such as pemphigus. However, a certain proportion of patients does not respond well to GCs. Although studies on the relationship between cytokines and GC insensitivity in local tissues have attracted attention recently, little is known about the underlying mechanism(s) for GC insensitivity in epidermal keratinocytes. Here, we report that tumor necrosis factor (TNF) alpha reduces GC-induced transactivation of endogenous genes as well as a reporter plasmid which contains GC responsive element (GRE) in human epidermal keratinocyte cells (HaCaT). The GC insensitivity by TNFalpha was not accompanied by changes in mRNA expressions of GR isoforms (alpha or beta). However, we observed that mitogen-activated protein kinase kinase-1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors (PD98059 and U0126) significantly sensitized the GC-induced transactivation of anti-inflammatory genes (glucocorticoid-induced leucine zipper (GILZ) and mitogen-activated protein kinase phosphatase (MKP)-1) and FK506 binding protein (FKBP) 51 gene in the presence of TNFalpha. Additionally, we observed that TNFalpha reduced prednisolone (PSL)-dependent nuclear translocation of GR, which was restored by pre-treatment of MEK-1 inhibitors. This is the first study demonstrating a role of the MEK-1/ERK cascade in TNFalpha-mediated GC insensitivity. Our data suggest that overexp…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Additional mechanisms that may be involved in STAT5-induced inhibition of GR function include disruption of GR translocation.
“Additional mechanisms that may be involved in STAT5-induced inhibition of GR function are believed to include disruption of GR translocation.56”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [56]
STAT5 and GR form complexes in the nucleus that ultimately disrupt GR-DNA binding.
“Studies using immunoprecipitation have demonstrated that STAT5 and GR form complexes in the nucleus that ultimately disrupt GR-DNA binding (Fig. 2).”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [56]
No citation lists for this paper
No citation lists for this paper yet — checked again daily.
References 32 · Cited by 28
- Authors
- Onda, K., Nagashima, M., Kawakubo, Y., Inoue, S., Hirano, T., & Oka, K.
- Affiliations
- Tokyo University of Pharmacy and Life Sciences (JP)
- Teikyo University (JP)
- Corresponding author
- Onda, Kenji
- ORCID
- Inoue, Shota
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2006-12
- Volume
- 351
- Issue
- 1
- Pages
- 266-272
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2012651444
- Cited by
- 28
- References
- 32
- Citations by year
- 2023: 1 · 2019: 2 · 2018: 3 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 3 · 2012: 4
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Research Foundation for Clinical Pharmacology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
- Keywords
- glucocorticoid resistance, TNF-α, glucocorticoid receptor, nuclear translocation, epidermal keratinocytes, GILZ, MKP-1, FKBP51, prednisolone, topical corticosteroids, pemphigus, PD98059, U0126
- MeSH terms
- Cell Line, Dose-Response Relationship, Drug, Glucocorticoids, Humans, Receptors, Glucocorticoid, Tumor Necrosis Factor-alpha, Keratinocytes, MAP Kinase Signaling System, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Kinase 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 ›
Are you an author, or do you see a problem with this page? Request a review
