Local glucocorticoid production in the mouse lung is induced by immune cell stimulation

Allergy. 2012 Feb;67(2):227-34. doi: 10.1111/j.1398-9995.2011.02749.x. Epub 2011 Nov 24.

Abstract

Background: Glucocorticoids (GC) are potent anti-inflammatory and immunosuppressive steroid hormones, mainly produced by the adrenal glands. However, increasing evidence supports the idea of additional extra-adrenal sources of bioactive GC. The lung epithelium is constantly exposed to a plethora of antigenic stimuli, and local GC synthesis could contribute to limit uncontrolled immune reactions and tissue damage.

Methods: Expression of steroidogenic enzymes and GC synthesis in ex vivo organ cultures was studied in mouse lung tissue after in vivo stimulation of immune cells.

Results: Mouse lung tissue was found to express steroidogenic enzymes required for the synthesis of corticosterone from cholesterol and to synthesize corticosterone in large quantities after immune cell activation by anti-CD3 antibody, lipopolysaccharide, or TNFα. In marked contrast, ovalbumin-induced allergic airway inflammation failed to promote lung GC synthesis. Although the lung expresses all steroidogenic enzymes necessary for de novo synthesis of corticosterone from cholesterol, functional data indicated that inactive serum-derived dehydrocorticosterone is converted to active corticosterone by 11β-hydroxysteroid dehydrogenase 1.

Conclusion: Our results support the notion that local GC synthesis represents a novel immunoregulatory mechanism to limit uncontrolled immune responses in the lung and indicate that defective local steroidogenesis may contribute to the pathogenesis of allergic airway inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Glucocorticoids / biosynthesis*
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Lung / immunology*
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Respiratory Hypersensitivity / genetics
  • Respiratory Hypersensitivity / immunology*
  • Respiratory Hypersensitivity / metabolism*
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Glucocorticoids
  • NR5A2 protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Tumor Necrosis Factor-alpha
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Steroid Hydroxylases
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