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Cited by 461Inflammatory mediators and NSAID effectsAdrenal Hormones and DisordersEicosanoids and Hypertension Pharmacology

Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme

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Masferrer, J L, Seibert, K, Zweifel, B, Needleman, P·1992·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.89.9.3917PMC PMC525602
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Abstract

The effect of endogenous glucocorticoids on the expression of the cyclooxygenase enzyme was studied by contrasting cyclooxygenase expression and prostanoid synthesis in adrenalectomized and sham-adrenalectomized mice with or without the concurrent administration of endotoxin. Peritoneal macrophages obtained from adrenalectomized mice showed a 2- to 3-fold induction in cyclooxygenase synthesis and activity when compared to sham controls. Intravenous injection of a sublethal dose of endotoxin (5 micrograms/kg) further stimulated cyclooxygenase synthesis, resulting in a 4-fold increase in prostaglandin production. Similar cyclooxygenase induction can be achieved in macrophages obtained from normal mice but only after high doses of endotoxin (2.5 mg/kg) that are 100% lethal to adrenalectomized mice. Restoration of glucocorticoids in adrenalectomized animals with dexamethasone completely inhibited the elevated cyclooxygenase and protected these animals from endotoxin-induced death. In contrast, no signs of cyclooxygenase induction were observed in the kidneys of the adrenalectomized mice, even when treated with endotoxin. Dexamethasone did not affect the constitutive cyclooxygenase activity and prostaglandin production present in normal and adrenalectomized kidneys. These data indicate the existence of a constitutive cyclooxygenase that is normally present in most cells and tissues and is unaffected by steroids and of an inducible cyclooxygenase that is expressed only in the context of inflammation by proinflammatory cells, like macrophages, and that is under glucocorticoid regulation. Under normal physiological conditions glucocorticoids maintain tonic inhibition of inducible cyclooxygenase expression. Depletion of glucocorticoids or the presence of an inflammatory stimulus such as endotoxin causes rapid induction of this enzyme, resulting in an exacerbated inflammatory response that is often lethal.

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  • Exacerbated levels of pro-inflammatory cytokines were found in the brain of adrenalectomized mice following a subcutaneous injection of LPS.

    “Almost 20 years ago, exacerbated levels of pro-inflammatory cytokines were found in the brain of adrenalectomized mice following a sub-cutaneous injection of LPS (127–130).”

    From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [130]

  • Substantial evidence established that GCs restrain and/or terminate the innate immune response in the CNS following either a peripheral or cerebral challenge.

    “Substantial evidence established that GCs restrain and/or terminate the innate immune response in the CNS following either a peripheral or cerebral challenge.”

    From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [130]

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Research works printed but not linked: 5

  1. [5]Geller, P., Merril, E. R. & Jawetz, E. (1954) Proc. Soc. Exp. Biol. Med. 86, 716–722.
  2. [8]Raz, A., Wyche, A. & Needleman, P. (1989) Proc. Natl. Acad. Sci. USA 86, 1657–1661.
  3. [12]Seibert, K., Masferrer, J. L., Fu, J. Y., Honda, A., Raz, A. & Needleman, P. (1990) in Advances in Prostaglandin, Thromboxane, and Leukotriene Research, eds. Samuelsson, B., Dahlén, S.-E., Fritsch, J. & Hedquist, P. (Raven, New York), Vol. 21, pp. 45–51.
  4. [16]Sebaldt, R. J., Sheller, J. R., Oates, J., Roberts, L. J., II, & Fitzgerald, G. A. (1990) Proc. Natl. Acad. Sci. USA 87, 6974-6978.
  5. [23]Xie, W., Chipman, J. G., Robertson, D. L., Erikson, R. L. & Simmons, D. L. (1991) Proc. Natl. Acad. Sci. USA 88, 2692– 2696.

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Authors
Masferrer, J. L., Seibert, K., Zweifel, B., & Needleman, P.
Affiliations
Monsanto (United States) (US)
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1992-05
Volume
89
Issue
9
Pages
3917-3921
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.89.9.3917
PMC
PMC525602
OpenAlex
W2015371826
Cited by
461
References
24
Citations by year
2025: 4 · 2024: 3 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 1 · 2018: 7 · 2017: 1 · 2016: 3 · 2015: 6 · 2014: 6 · 2013: 8 · 2012: 7
FWCI
30.54
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
Keywords
glucocorticoids, cyclooxygenase, adrenalectomy, endotoxin, peritoneal macrophages, prostaglandin synthesis, dexamethasone, inflammation
MeSH terms
Adrenalectomy, Animals, Dexamethasone, Enzyme Induction, Glucocorticoids, Indomethacin, Kidney, Lipopolysaccharides, Macrophages, Mice, Inbred BALB C, Peritoneal Cavity, Precipitin Tests, Prostaglandin-Endoperoxide Synthases, Thromboxane B2, 6-Ketoprostaglandin F1 alpha, Dinoprostone, Eicosanoids, Mice

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