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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: Stimulating GMC with IL-1beta or TNF-alpha increased expression and reductase activity of 11beta-OHSD1.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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Related in: MedlinePlus

GA enhances the  ability of corticosterone (Cort) to  inhibit IL-1β– and forskolin– induced phospholipase (PLA2)  activity. (Top) GMC were incubated for 48 h with combinations  of IL-1β (5 nM), corticosterone  (50 nM), and glycyrrhetinic acid  (5 μM), and PLA2 assays were  performed. Results represent  the mean (± SD) of three assays.  (Bottom) Inhibition of group II  PLA2 enzyme activity in forskolin stimulated GMC. Each column represents the mean (± SD)  of three determinations. The inhibition of the enzyme activity  by corticosterone was enhanced  by the addition of GA.
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Figure 5: GA enhances the ability of corticosterone (Cort) to inhibit IL-1β– and forskolin– induced phospholipase (PLA2) activity. (Top) GMC were incubated for 48 h with combinations of IL-1β (5 nM), corticosterone (50 nM), and glycyrrhetinic acid (5 μM), and PLA2 assays were performed. Results represent the mean (± SD) of three assays. (Bottom) Inhibition of group II PLA2 enzyme activity in forskolin stimulated GMC. Each column represents the mean (± SD) of three determinations. The inhibition of the enzyme activity by corticosterone was enhanced by the addition of GA.

Mentions: In line with these observations, the enzymatic activity of PLA2 increased upon stimulation with IL-1β or forskolin, to be then decreased by the action of corticosterone and corticosterone combined with GA (Fig. 5). Corticosterone reduced the IL-1β–stimulated PLA2 enzyme activity by 60% and corticosterone in combination with GA diminished the activity by 90% (Fig. 5, top). GA alone did not alter the secretion of PLA2 induced by IL-1β (Fig. 5, top). Similar results were obtained when forskolin, instead of IL-1β, was used for stimulaton of group II PLA2 activity (Fig. 5, bottom).


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)

GA enhances the  ability of corticosterone (Cort) to  inhibit IL-1β– and forskolin– induced phospholipase (PLA2)  activity. (Top) GMC were incubated for 48 h with combinations  of IL-1β (5 nM), corticosterone  (50 nM), and glycyrrhetinic acid  (5 μM), and PLA2 assays were  performed. Results represent  the mean (± SD) of three assays.  (Bottom) Inhibition of group II  PLA2 enzyme activity in forskolin stimulated GMC. Each column represents the mean (± SD)  of three determinations. The inhibition of the enzyme activity  by corticosterone was enhanced  by the addition of GA.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198986&req=5

Figure 5: GA enhances the ability of corticosterone (Cort) to inhibit IL-1β– and forskolin– induced phospholipase (PLA2) activity. (Top) GMC were incubated for 48 h with combinations of IL-1β (5 nM), corticosterone (50 nM), and glycyrrhetinic acid (5 μM), and PLA2 assays were performed. Results represent the mean (± SD) of three assays. (Bottom) Inhibition of group II PLA2 enzyme activity in forskolin stimulated GMC. Each column represents the mean (± SD) of three determinations. The inhibition of the enzyme activity by corticosterone was enhanced by the addition of GA.
Mentions: In line with these observations, the enzymatic activity of PLA2 increased upon stimulation with IL-1β or forskolin, to be then decreased by the action of corticosterone and corticosterone combined with GA (Fig. 5). Corticosterone reduced the IL-1β–stimulated PLA2 enzyme activity by 60% and corticosterone in combination with GA diminished the activity by 90% (Fig. 5, top). GA alone did not alter the secretion of PLA2 induced by IL-1β (Fig. 5, top). Similar results were obtained when forskolin, instead of IL-1β, was used for stimulaton of group II PLA2 activity (Fig. 5, bottom).

Bottom Line: Stimulating GMC with IL-1beta or TNF-alpha increased expression and reductase activity of 11beta-OHSD1.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