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Effect of inflammation on local metabolism of glucocorticoids in neuroendocrine regulatory pathways and secondary lymphoid organs

Glucocorticoids exert anti-inflammatory and immunomodulatory effects that may be regulated in part by the activities of the glucocorticoid-activating and -inactivating enzymes, 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) and type 2 (11HSD2), respectively. Exposure to proinflammatory stimuli such as TNF-α and IL-1β increases 11HSD1 in some cells, while inducing a decrease of 11HSD2 in others. These findings indicate that changes in 11HSD activity induced by proinflammatory cytokines might contribute to the feedback regulation of inflammation. The aim of the project is therefore to improve our understanding of the role of 11HSDs in inflammation.

Inflammation is a first-line host defense mechanism of the innate immune system for removing invading pathogens and repairing damaged tissues. In response to inflammation, the increase in circulating proinflammatory cytokines triggers a feedback loop, which stimulates the synthesis and secretion of glucocorticoids by the adrenal gland. Glucocorticoids are steroid hormones that are known to modulate various immune and inflammatory functions. Both natural and synthetic glucocorticoids have been shown to possess clinical efficacy as anti-inflammatory agents and many immune-mediated diseases are commonly treated with these steroids. The bioavailability of biologically active glucocorticoids is controlled by the intracellular enzyme 11β-hydroxysteroid dehydrogenase (11HSD), which has two types – 11HSD1 and 11HSD2. Type 11HSD2 acts exclusively as a dehydrogenase that converts the biologically active glucocorticoids, cortisol and corticosterone, into their inactive 11-oxo derivatives, cortisone and 11-dehydrocorticosterone, respectively, whereas 11HSD1 predominantly mediates the reduction of the 11-oxo derivatives. It is not currently known whether proinflammatory cytokines alter 11HSDs and whether inflammation modulates glucocorticoid metabolism in lymphoid organs.

 The scope of this project is

(1) to ascertain whether inflammation modulates local metabolism of glucocorticoids in lymphoid organs

(2) to determine what is the mechanism, which leads to the effect of proinflammatory cytokines on regulation of 11HSDs.


Recent  publications

Ergang P, Vytáčková K, Svec J, Bryndová J, Mikšík I, Pácha J. Upregulation of 11β-hydroxysteroid dehydrogenase 1 in lymphoid organs during inflammation in the rat. J Steroid Biochem Mol Biol 126:19-25, 2011

Vagnerová K, Loukotová J, Ergang P, Musílková J, Mikšík I, Pácha J. Peroxisome proliferator-activated receptor-γ stimulates 11β-hydroxysteroid dehydrogenase type 1 in rat vascular smooth muscle cells. Steroids 76:577-81, 2011

Ergang P, Leden P, Vagnerová K, Klusoňová P, Mikšík I, Jurčovičová J, Kment M, Pácha J. Local metabolism of glucocorticoids and its role in rat adjuvant arthritis. Mol Cell Endocrinol 323:155-60, 2010.