Journal
ENDOCRINOLOGY
Volume 153, Issue 1, Pages 234-240Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2011-1398
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Funding
- Medical Research Council [G0800235]
- Wellcome Trust [WT083184, WT064497]
- Arthritis Research Campaign Clinician Scientist Fellowship
- MRC [G0901697, G0800235] Funding Source: UKRI
- Medical Research Council [G9900991B, G0901697, G0800235] Funding Source: researchfish
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Glucocorticoids profoundly influence immune responses, and synthetic glucocorticoids are widely used clinically for their potent antiinflammatory effects. Endogenous glucocorticoid action is modulated by the two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). In vivo, 11 beta-HSD1 catalyzes the reduction of inactive cortisone or 11-dehydrocorticosterone into active cortisol or corticosterone, respectively, thereby increasing intracellular glucocorticoid levels. 11 beta-HSD2 catalyzes the reverse reaction, inactivating intracellular glucocorticoids. Both enzymes have been postulated to modulate inflammatory responses. In the K/BxN serum transfer model of arthritis, 11 beta-HSD1-deficient mice showed earlier onset and slower resolution of inflammation than wildtype controls, with greater exostoses in periarticular bone and, uniquely, ganglion cysts, consistent with greater inflammation. In contrast, K/BxN serum arthritis was unaffected by 11 beta-HSD2 deficiency. In a distinct model of inflammation, thioglycollate-induced sterile peritonitis, 11 beta-HSD1-deficient mice had more inflammatory cells in the peritoneum, but again 11 beta-HSD2-deficient mice did not differ from controls. Additionally, compared with control mice, 11 beta-HSD1-deficient mice showed greater numbers of inflammatory cells in pleural lavages in carrageenan-induced pleurisy with lung pathology consistent with slower resolution. These data suggest that 11 beta-HSD1 limits acute inflammation. In contrast, 11 beta-HSD2 plays no role in acute inflammatory responses in mice. Regulation of local 11 beta-HSD1 expression and/or delivery of substrate may afford a novel approach for antiinflammatory therapy. (Endocrinology 153: 234-240, 2012)
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