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Tumor necrosis factor alpha and interleukin 1beta enhance the cortisone/cortisol shuttle.

Escher G, Galli I, Vishwanath BS, Frey BM, Frey FJ - J. Exp. Med. (1997)

Bottom Line: Since we found that glomerular mesangial cells (GMC) express 11beta-hydroxysteroid dehydrogenase 1 (11beta-OHSD1), which interconverts 11-keto glucocorticosteroids into 11beta-hydroxy glucocorticosteroids (cortisone/cortisol shuttle), we explored whether 11beta-OHSD1 determines the antiinflammatory effect of glucocorticosteroids.Thus, we conclude that 11beta-OHSD1 controls access of 11beta-hydroxy glucocorticosteroids and 11-keto glucocorticosteroids to glucocorticoid receptors and thus determines the anti-inflammatory effect of glucocorticosteroids.IL-1beta and TNF-alpha upregulate specifically the reductase activity of 11beta-OHSD1 and counterbalance by that mechanism their own proinflammatory effect.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, University Hospital of Berne, 3010 Berne, Switzerland.

ABSTRACT
Endogenously released or exogenously administered glucocorticosteroids are relevant hormones for controlling inflammation. Only 11beta-hydroxy glucocorticosteroids, but not 11-keto glucocorticosteroids, activate glucocorticoid receptors. Since we found that glomerular mesangial cells (GMC) express 11beta-hydroxysteroid dehydrogenase 1 (11beta-OHSD1), which interconverts 11-keto glucocorticosteroids into 11beta-hydroxy glucocorticosteroids (cortisone/cortisol shuttle), we explored whether 11beta-OHSD1 determines the antiinflammatory effect of glucocorticosteroids. GMC exposed to interleukin (IL)-1beta or tumor necrosis factor alpha (TNF-alpha) release group II phospholipase A2 (PLA2), a key enzyme producing inflammatory mediators. 11beta-hydroxy glucocorticosteroids inhibited cytokine-induced transcription and release of PLA2 through a glucocorticoid receptor-dependent mechanism. This inhibition was enhanced by inhibiting 11beta-OHSD1. Interestingly, 11-keto glucocorticosteroids decreased cytokine-induced PLA2 release as well, a finding abrogated by inhibiting 11beta-OHSD1. Stimulating GMC with IL-1beta or TNF-alpha increased expression and reductase activity of 11beta-OHSD1. Similarly, this IL-1beta- and TNF-alpha-induced formation of active 11beta-hydroxy glucocorticosteroids from inert 11-keto glucocorticosteroids by the 11beta-OHSD1 was shown in the Kiki cell line that expresses the stably transfected bacterial beta-galactosidase gene under the control of a glucocorticosteroids response element. Thus, we conclude that 11beta-OHSD1 controls access of 11beta-hydroxy glucocorticosteroids and 11-keto glucocorticosteroids to glucocorticoid receptors and thus determines the anti-inflammatory effect of glucocorticosteroids. IL-1beta and TNF-alpha upregulate specifically the reductase activity of 11beta-OHSD1 and counterbalance by that mechanism their own proinflammatory effect.

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Cortisone/cortisol shuttle. The endogenous hormones cortisol and corticosterone, as well as the pharmacologically used prednisolone,  are biologically active 11β-hydroxy glucocorticosteroids because they can  bind to the cognate receptor. The corresponding 11-keto glucocorticoids  cortisone, dehydrocorticosterone, and prednisone are unable to do so.  The enzyme 11β-OHSD1 converts 11-keto glucocorticosteroids to 11β-hydroxy glucocorticosteroids and vice versa, and thus regulates local intracellular access of the steroids to the receptors. 11β-OHSD activity can  be inhibited by glycyrrhetinic acid, a compound found in licorice and anise. Corticosterone and dehydrocorticosterone differ from cortisol and  cortisone because of the absence of a hydroxyl group at position C17,  whereas prednisolone and prednisone have an additional double bond in the  A ring.
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Figure 1: Cortisone/cortisol shuttle. The endogenous hormones cortisol and corticosterone, as well as the pharmacologically used prednisolone, are biologically active 11β-hydroxy glucocorticosteroids because they can bind to the cognate receptor. The corresponding 11-keto glucocorticoids cortisone, dehydrocorticosterone, and prednisone are unable to do so. The enzyme 11β-OHSD1 converts 11-keto glucocorticosteroids to 11β-hydroxy glucocorticosteroids and vice versa, and thus regulates local intracellular access of the steroids to the receptors. 11β-OHSD activity can be inhibited by glycyrrhetinic acid, a compound found in licorice and anise. Corticosterone and dehydrocorticosterone differ from cortisol and cortisone because of the absence of a hydroxyl group at position C17, whereas prednisolone and prednisone have an additional double bond in the A ring.

Mentions: IL-1β and TNF-α often act synergistically and cause a wide array of in vitro and in vivo immune inflammatory responses such as the secretion of phospholipase A2 (PLA2)1, a key enzyme that releases arachidonic acid and therefore boosts prostaglandin production and secretion (1–3). This inflammatory reaction is regulated by 11β-hydroxy glucocorticosteroids; for instance, glucocorticoid deficiency increases, whereas physiological and pharmacological doses of glucocorticosteroids suppress the enhanced expression of group II PLA2 during inflammation (4–7). The biological activity of glucocorticosteroids depends on their dose, metabolism, local access to their cognate receptors, and on the responsiveness of the target cells (8, 9). Traditionally the 11-keto– glucocorticosteroid molecules are believed to have hardly any biological activity because of their negligible affinity to glucocorticoid receptors. In the present investigation, we demonstrate that during inflammation, 11-keto steroids exhibit antiinflammatory properties. This effect is dependent on the activity of the enzyme 11β-hydroxysteroid dehydrogenase (11β-OHSD), which interconverts the 11-keto and the corresponding 11β-hydroxy glucocorticosteroids by the so-called cortisone/cortisol shuttle (8, 10–15; Fig. 1).


Tumor necrosis factor alpha and interleukin 1beta enhance the cortisone/cortisol shuttle.

Escher G, Galli I, Vishwanath BS, Frey BM, Frey FJ - J. Exp. Med. (1997)

Cortisone/cortisol shuttle. The endogenous hormones cortisol and corticosterone, as well as the pharmacologically used prednisolone,  are biologically active 11β-hydroxy glucocorticosteroids because they can  bind to the cognate receptor. The corresponding 11-keto glucocorticoids  cortisone, dehydrocorticosterone, and prednisone are unable to do so.  The enzyme 11β-OHSD1 converts 11-keto glucocorticosteroids to 11β-hydroxy glucocorticosteroids and vice versa, and thus regulates local intracellular access of the steroids to the receptors. 11β-OHSD activity can  be inhibited by glycyrrhetinic acid, a compound found in licorice and anise. Corticosterone and dehydrocorticosterone differ from cortisol and  cortisone because of the absence of a hydroxyl group at position C17,  whereas prednisolone and prednisone have an additional double bond in the  A ring.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2198986&req=5

Figure 1: Cortisone/cortisol shuttle. The endogenous hormones cortisol and corticosterone, as well as the pharmacologically used prednisolone, are biologically active 11β-hydroxy glucocorticosteroids because they can bind to the cognate receptor. The corresponding 11-keto glucocorticoids cortisone, dehydrocorticosterone, and prednisone are unable to do so. The enzyme 11β-OHSD1 converts 11-keto glucocorticosteroids to 11β-hydroxy glucocorticosteroids and vice versa, and thus regulates local intracellular access of the steroids to the receptors. 11β-OHSD activity can be inhibited by glycyrrhetinic acid, a compound found in licorice and anise. Corticosterone and dehydrocorticosterone differ from cortisol and cortisone because of the absence of a hydroxyl group at position C17, whereas prednisolone and prednisone have an additional double bond in the A ring.
Mentions: IL-1β and TNF-α often act synergistically and cause a wide array of in vitro and in vivo immune inflammatory responses such as the secretion of phospholipase A2 (PLA2)1, a key enzyme that releases arachidonic acid and therefore boosts prostaglandin production and secretion (1–3). This inflammatory reaction is regulated by 11β-hydroxy glucocorticosteroids; for instance, glucocorticoid deficiency increases, whereas physiological and pharmacological doses of glucocorticosteroids suppress the enhanced expression of group II PLA2 during inflammation (4–7). The biological activity of glucocorticosteroids depends on their dose, metabolism, local access to their cognate receptors, and on the responsiveness of the target cells (8, 9). Traditionally the 11-keto– glucocorticosteroid molecules are believed to have hardly any biological activity because of their negligible affinity to glucocorticoid receptors. In the present investigation, we demonstrate that during inflammation, 11-keto steroids exhibit antiinflammatory properties. This effect is dependent on the activity of the enzyme 11β-hydroxysteroid dehydrogenase (11β-OHSD), which interconverts the 11-keto and the corresponding 11β-hydroxy glucocorticosteroids by the so-called cortisone/cortisol shuttle (8, 10–15; Fig. 1).

Bottom Line: Since we found that glomerular mesangial cells (GMC) express 11beta-hydroxysteroid dehydrogenase 1 (11beta-OHSD1), which interconverts 11-keto glucocorticosteroids into 11beta-hydroxy glucocorticosteroids (cortisone/cortisol shuttle), we explored whether 11beta-OHSD1 determines the antiinflammatory effect of glucocorticosteroids.Thus, we conclude that 11beta-OHSD1 controls access of 11beta-hydroxy glucocorticosteroids and 11-keto glucocorticosteroids to glucocorticoid receptors and thus determines the anti-inflammatory effect of glucocorticosteroids.IL-1beta and TNF-alpha upregulate specifically the reductase activity of 11beta-OHSD1 and counterbalance by that mechanism their own proinflammatory effect.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, University Hospital of Berne, 3010 Berne, Switzerland.

ABSTRACT
Endogenously released or exogenously administered glucocorticosteroids are relevant hormones for controlling inflammation. Only 11beta-hydroxy glucocorticosteroids, but not 11-keto glucocorticosteroids, activate glucocorticoid receptors. Since we found that glomerular mesangial cells (GMC) express 11beta-hydroxysteroid dehydrogenase 1 (11beta-OHSD1), which interconverts 11-keto glucocorticosteroids into 11beta-hydroxy glucocorticosteroids (cortisone/cortisol shuttle), we explored whether 11beta-OHSD1 determines the antiinflammatory effect of glucocorticosteroids. GMC exposed to interleukin (IL)-1beta or tumor necrosis factor alpha (TNF-alpha) release group II phospholipase A2 (PLA2), a key enzyme producing inflammatory mediators. 11beta-hydroxy glucocorticosteroids inhibited cytokine-induced transcription and release of PLA2 through a glucocorticoid receptor-dependent mechanism. This inhibition was enhanced by inhibiting 11beta-OHSD1. Interestingly, 11-keto glucocorticosteroids decreased cytokine-induced PLA2 release as well, a finding abrogated by inhibiting 11beta-OHSD1. Stimulating GMC with IL-1beta or TNF-alpha increased expression and reductase activity of 11beta-OHSD1. Similarly, this IL-1beta- and TNF-alpha-induced formation of active 11beta-hydroxy glucocorticosteroids from inert 11-keto glucocorticosteroids by the 11beta-OHSD1 was shown in the Kiki cell line that expresses the stably transfected bacterial beta-galactosidase gene under the control of a glucocorticosteroids response element. Thus, we conclude that 11beta-OHSD1 controls access of 11beta-hydroxy glucocorticosteroids and 11-keto glucocorticosteroids to glucocorticoid receptors and thus determines the anti-inflammatory effect of glucocorticosteroids. IL-1beta and TNF-alpha upregulate specifically the reductase activity of 11beta-OHSD1 and counterbalance by that mechanism their own proinflammatory effect.

Show MeSH
Related in: MedlinePlus