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Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme
J L Masferrer1, K Seibert, B Zweifel
1Department of Molecular Pharmacology, Monsanto Company T3G, St. Louis, MO 63167.
Summary
Glucocorticoids normally inhibit inducible cyclooxygenase (COX) in macrophages. Depleting these steroids or adding endotoxin rapidly increases COX, worsening inflammation and potentially causing death.
Area of Science:
- Endocrinology
- Immunology
- Inflammation Research
Background:
- Endogenous glucocorticoids play a crucial role in regulating inflammatory responses.
- Cyclooxygenase (COX) enzymes are key mediators of inflammation through prostanoid synthesis.
Purpose of the Study:
- To investigate the impact of endogenous glucocorticoids on cyclooxygenase expression and prostanoid synthesis.
- To differentiate between constitutive and inducible forms of cyclooxygenase.
Main Methods:
- Comparison of COX expression and prostanoid synthesis in adrenalectomized and sham-adrenalectomized mice.
- Administration of endotoxin to assess inflammatory response modulation.
- Treatment with dexamethasone to evaluate glucocorticoid restoration effects.
Main Results:
- Adrenalectomized mice exhibited significantly higher COX synthesis and activity in macrophages compared to controls.
- Endotoxin further increased COX synthesis and prostaglandin production in macrophages, with higher lethality in adrenalectomized mice.
- Dexamethasone administration inhibited elevated COX, protected against endotoxin-induced death, and did not affect kidney COX activity.
Conclusions:
- Two forms of COX exist: a constitutive form unaffected by steroids and an inducible form in macrophages regulated by glucocorticoids.
- Glucocorticoids tonically inhibit inducible COX expression under normal conditions.
- Glucocorticoid depletion or inflammatory stimuli like endotoxin lead to rapid COX induction, exacerbating inflammation and potentially causing death.