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Cited by 378Estrogen and related hormone effectsReceptor Mechanisms and SignalingAdrenal Hormones and Disorders

Ligand-independent Activation of the Glucocorticoid Receptor by β2-Adrenergic Receptor Agonists in Primary Human Lung Fibroblasts and Vascular Smooth Muscle Cells

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Eickelberg, Oliver, Roth, Michael, Lörx, Rainer, Bruce, Victoria, Rüdiger, Jochen, Johnson, Malcolm, Block, Lutz-Henning·1999·Journal of Biological Chemistry
DOI 10.1074/jbc.274.2.1005
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Abstract

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor present in most cell types. Upon ligand binding, the GR is activated and translocates into the nucleus where it transmits the anti-inflammatory actions of glucocorticoids. Here, we describe the ligand-independent activation of GR by the beta2-adrenergic receptor (beta2-AR) agonists, salbutamol and salmeterol, in primary human lung fibroblasts and vascular smooth muscle cells. Immunohistochemistry demonstrated expression of GR and the beta2-AR by fibroblasts and vascular smooth muscle cells. Treatment of the cells with the beta2-AR agonists, salbutamol or salmeterol, resulted in translocation of GR into the nucleus beginning at 30 min, as shown by immunohistochemistry and Western blotting of cytosolic and nuclear cell extracts. In comparison, activation of GR induced by the corticosteroids dexamethasone and fluticasone occurred at the same time after treatment (30 min) but resulted in a more complete depletion of GR from the cytosolic compartment. Electrophoretic mobility shift assays confirmed that nuclear GR, activated by both beta2-AR agonists and glucocorticoids, actively bound to the GR consensus sequence (GR element). Functional activation of the GR was confirmed by a Luciferase reporter gene assay, using a GR driven promoter fragment from the p21((WAF1/CIP1)) gene. The effects of the beta2-AR agonists, salbutamol and salmeterol, were dependent upon binding to the beta2-AR, because blocking of beta2-AR with propranolol abrogated GR activation. GR activation appeared to involve cAMP. In summary, these data show that beta2-AR agonists are potent activators of GR. Ligand-independent activation of GR by beta2-AR agonists may substantially mediate the anti-inflammatory actions of these drugs observed in vitro and in vivo.

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Crossref · 10.1074/jbc.274.2.1005

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  • PKA activates GR function in a ligand-independent manner.

    “PKA also activates GR function in a ligand-independent manner.111”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [111]

    The Discussion (p. 5) demonstrates ligand-independent, functional GR activation by β2-adrenergic agonists. The Results (p. 4) report that a PKA-inhibiting peptide partly reduced this activation, and the Discussion (p. 6) describes PKA-pathway involvement as possible rather than establishing that PKA itself activates GR. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • In the same study, addition of cAMP alone induced GR-GRE binding and a PKA-inhibiting peptide reduced this effect.

    “In the same study, addition of cAMP alone was also shown to induce GR-GRE binding and a PKA-inhibiting peptide reduced this effect.”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [111]

    The Results (p. 4) report that two cAMP mimetics induced GR–GRE binding. But the PKA-inhibiting peptide was tested against salmeterol-induced GR activation, not cAMP-induced binding, so the source does not establish that it reduced the effect of cAMP alone. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Treatment of human lung fibroblasts and vascular smooth muscle cells with β2 adrenergic receptor agonists salbutamol or salmeterol initiates GR translocation from cytoplasm to nucleus, increases GR-DNA binding, and increases GR-mediated gene transcription.

    “Treatment of human lung fibroblasts and vascular smooth muscle cells with the β2 adrenergic receptor agonists, salbutamol or salmeterol, was found to initiate GR translocation from cytoplasm to nucleus, increase GR-DNA binding, and increase GR-mediated gene transcription.111”

    From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [111]

  • Antidepressants induce GR nuclear translocation and transactivation, at least in part mediated by the cAMP/PKA cascade.

    “Studies by us and others have shown that antidepressants also induce GR nuclear translocation and transactivation, which is, at least in part, mediated by the cyclic AMP (cAMP)/protein kinase A (PKA) cascade.21, 22, 23, 24, 30, 31, 32, 33”

    From Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor (2011) · cites this paper as [32]

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Research works printed but not linked: 6

  1. [4]4. Dahlmann-Wright, K., Almlo ¨f, T., McEwan, I. J., Gustafsson, J.-A., and Wright, A. P. H. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 1619-1623
  2. [15]15. Kobilka, B. K., Dixon, R. A. F., Frielle, T., Dohlman, H. G., Bolanowski, M. A., Sigal, I. S., Yang-Feng, T. L., Francke, U., Caron, M. G., and Lefkowitz, R. J. (1987) Proc. Natl. Acad. Sci. U. S. A. 84, 46-50
  3. [21]21. Roth, M., Eickelberg, O., Ko ¨hler, E., Erne, P., and Block, L. H. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 5478-5482
  4. [30]30. Hadcock, J. R., and Malbon, C. C. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 8415-8419
  5. [42]42. Bredt, D. S., and Snyder, S. H. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 682-687
  6. [44]44. Migliaccio, A., Rotondi, A., and Auricchio, F. (1984) Proc. Natl. Acad. Sci. U. S. A. 81, 5921-5925

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Authors
Eickelberg, O., Roth, M., Lörx, R., Bruce, V., Rüdiger, J., Johnson, M., & Block, L.-H.
Affiliations
  • University Hospital of Basel (CH)
  • University of Vienna (AT)
Corresponding author
Block, Lutz-Henning
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1999-01
Volume
274
Issue
2
Pages
1005-1010
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.274.2.1005
OpenAlex
W1995257163
Cited by
378
References
43
Citations by year
2025: 3 · 2024: 2 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 1 · 2019: 5 · 2018: 9 · 2017: 2 · 2016: 8 · 2015: 11 · 2014: 11 · 2013: 10 · 2012: 17
FWCI
14.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
glucocorticoid receptor, ligand-independent receptor activation, beta2-adrenergic agonists, salbutamol, salmeterol, lung fibroblasts, vascular smooth muscle cells, nuclear translocation, cAMP signaling, propranolol, anti-inflammatory activity
MeSH terms
Adrenergic beta-Agonists, Base Sequence, Cells, Cultured, Fibroblasts, Humans, Ligands, Lung, Muscle, Smooth, Vascular, Protein Binding, Receptors, Glucocorticoid, DNA Primers, Adrenergic beta-2 Receptor Agonists

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