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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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(a) 11-keto glucocorticosteroids are converted into active  compounds and drive glucocorticoid-dependent gene expression in Kiki  cells. Kiki cells were incubated with 11β-hydroxy glucocorticosteroids (far  left histogram), the corresponding 11-keto glucocorticosteroids alone (middle left historgram), and the 11-keto glucocorticosteroids with IL-1β in absence (middle right histogram) and presence (far right histogram) of GA. Expression of the bacterial β-galactosidase reporter gene was detected by an  in situ assay as described (21). Results represent the mean value (± SD) of  three independent assays. Concentrations: steroids, 0.1 μM; IL-1β, 5 nM;  GA, 50 μM. 11β-hydroxy glucocorticosteroids: cortisol, corticosterone,  prednisolone. 11-keto glucocorticosteroids: cortisone, dehydrocorticosterone, prednisone. Cortexolone, included in both keto and hydroxy groups,  does not carry a functional group at position 11, and is therefore not a  substrate for 11β-OHSD1. (b) Effect of GA on conversion of prednisone  (Pn) into prednisolone (Po). Kiki cells were incubated in the presence of  0.1 μM prednisolone alone (column 1), 0.1 μM prednisone alone (column 2), 0.1 μM prednisone + 5 nM IL-1β without GA (column 3), and  with 0.1, 1.0, and 10 μM GA (columns 4, 5, and 6). Results represent the  mean value (± SD) of three determinations.
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Figure 10: (a) 11-keto glucocorticosteroids are converted into active compounds and drive glucocorticoid-dependent gene expression in Kiki cells. Kiki cells were incubated with 11β-hydroxy glucocorticosteroids (far left histogram), the corresponding 11-keto glucocorticosteroids alone (middle left historgram), and the 11-keto glucocorticosteroids with IL-1β in absence (middle right histogram) and presence (far right histogram) of GA. Expression of the bacterial β-galactosidase reporter gene was detected by an in situ assay as described (21). Results represent the mean value (± SD) of three independent assays. Concentrations: steroids, 0.1 μM; IL-1β, 5 nM; GA, 50 μM. 11β-hydroxy glucocorticosteroids: cortisol, corticosterone, prednisolone. 11-keto glucocorticosteroids: cortisone, dehydrocorticosterone, prednisone. Cortexolone, included in both keto and hydroxy groups, does not carry a functional group at position 11, and is therefore not a substrate for 11β-OHSD1. (b) Effect of GA on conversion of prednisone (Pn) into prednisolone (Po). Kiki cells were incubated in the presence of 0.1 μM prednisolone alone (column 1), 0.1 μM prednisone alone (column 2), 0.1 μM prednisone + 5 nM IL-1β without GA (column 3), and with 0.1, 1.0, and 10 μM GA (columns 4, 5, and 6). Results represent the mean value (± SD) of three determinations.

Mentions: The biological relevance of the increased reductase activity of 11β-OHSD1 after stimulation with IL-1β and/or TNF-α was assessed first on the inhibition of PLA2 activity in GMC. Unstimulated GMC or GMC treated with GA alone or with the 11-keto–glucocorticosteroid dehydrocorticosterone alone displayed only background PLA2 activity (Fig. 9). Stimulation of GMC with IL-1β enhanced PLA2 production at least fivefold. Dehydrocorticosterone reduced the IL-1β–induced PLA2 activity. This effect was abrogated with increasing concentrations of GA (Fig. 9). In a second set of experiments, the relevance of the interconversion of biologically inactive 11-keto glycocorticosteroids into active 11β-hydroxy glucocorticosteroids was demonstrated in the Kiki cell line (21). We found that Kiki cells contain high levels of 11β-OHSD1, but low levels of 11β-OHSD2 transcripts (data not shown). TNF-α and IL-1β induce the reductase activity of 11β-OHSD1 in these cells (data not shown). Kiki cells express the bacterial β-galactosidase gene under the control of glucocorticoid-responsive elements of the mouse mammary tumor virus promoter. This cell line therefore expresses β-galactosidase only when biologically active 11β-hydroxy glucocorticosteroids are present. The experiments in Fig. 10 demonstrate that although 11β-hydroxy glucocorticosteroids directly drive gene expression, 11-keto glucocorticosteroids are unable to do so unless the cells are concomitantly stimulated by IL-1β. This effect is mediated by 11β-OHSD activity, because it can be abolished with GA in a dose dependent fashion (Fig. 10 b). Furthermore, this effect is specific for 11-keto glucocorticosteroids as cortexolone, a steroid without a functional group at position 11, displays an 11β-OHSD– and cytokine–independent constitutive activity, albeit weak (Fig. 10 a) The relevance of the conversion of cortisone to cortisol was furthermore shown when these two endogenous glucocorticosteroids are present in the low physiological concentration range using Kiki cells (data not shown).


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)

(a) 11-keto glucocorticosteroids are converted into active  compounds and drive glucocorticoid-dependent gene expression in Kiki  cells. Kiki cells were incubated with 11β-hydroxy glucocorticosteroids (far  left histogram), the corresponding 11-keto glucocorticosteroids alone (middle left historgram), and the 11-keto glucocorticosteroids with IL-1β in absence (middle right histogram) and presence (far right histogram) of GA. Expression of the bacterial β-galactosidase reporter gene was detected by an  in situ assay as described (21). Results represent the mean value (± SD) of  three independent assays. Concentrations: steroids, 0.1 μM; IL-1β, 5 nM;  GA, 50 μM. 11β-hydroxy glucocorticosteroids: cortisol, corticosterone,  prednisolone. 11-keto glucocorticosteroids: cortisone, dehydrocorticosterone, prednisone. Cortexolone, included in both keto and hydroxy groups,  does not carry a functional group at position 11, and is therefore not a  substrate for 11β-OHSD1. (b) Effect of GA on conversion of prednisone  (Pn) into prednisolone (Po). Kiki cells were incubated in the presence of  0.1 μM prednisolone alone (column 1), 0.1 μM prednisone alone (column 2), 0.1 μM prednisone + 5 nM IL-1β without GA (column 3), and  with 0.1, 1.0, and 10 μM GA (columns 4, 5, and 6). Results represent the  mean value (± SD) of three determinations.
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Figure 10: (a) 11-keto glucocorticosteroids are converted into active compounds and drive glucocorticoid-dependent gene expression in Kiki cells. Kiki cells were incubated with 11β-hydroxy glucocorticosteroids (far left histogram), the corresponding 11-keto glucocorticosteroids alone (middle left historgram), and the 11-keto glucocorticosteroids with IL-1β in absence (middle right histogram) and presence (far right histogram) of GA. Expression of the bacterial β-galactosidase reporter gene was detected by an in situ assay as described (21). Results represent the mean value (± SD) of three independent assays. Concentrations: steroids, 0.1 μM; IL-1β, 5 nM; GA, 50 μM. 11β-hydroxy glucocorticosteroids: cortisol, corticosterone, prednisolone. 11-keto glucocorticosteroids: cortisone, dehydrocorticosterone, prednisone. Cortexolone, included in both keto and hydroxy groups, does not carry a functional group at position 11, and is therefore not a substrate for 11β-OHSD1. (b) Effect of GA on conversion of prednisone (Pn) into prednisolone (Po). Kiki cells were incubated in the presence of 0.1 μM prednisolone alone (column 1), 0.1 μM prednisone alone (column 2), 0.1 μM prednisone + 5 nM IL-1β without GA (column 3), and with 0.1, 1.0, and 10 μM GA (columns 4, 5, and 6). Results represent the mean value (± SD) of three determinations.
Mentions: The biological relevance of the increased reductase activity of 11β-OHSD1 after stimulation with IL-1β and/or TNF-α was assessed first on the inhibition of PLA2 activity in GMC. Unstimulated GMC or GMC treated with GA alone or with the 11-keto–glucocorticosteroid dehydrocorticosterone alone displayed only background PLA2 activity (Fig. 9). Stimulation of GMC with IL-1β enhanced PLA2 production at least fivefold. Dehydrocorticosterone reduced the IL-1β–induced PLA2 activity. This effect was abrogated with increasing concentrations of GA (Fig. 9). In a second set of experiments, the relevance of the interconversion of biologically inactive 11-keto glycocorticosteroids into active 11β-hydroxy glucocorticosteroids was demonstrated in the Kiki cell line (21). We found that Kiki cells contain high levels of 11β-OHSD1, but low levels of 11β-OHSD2 transcripts (data not shown). TNF-α and IL-1β induce the reductase activity of 11β-OHSD1 in these cells (data not shown). Kiki cells express the bacterial β-galactosidase gene under the control of glucocorticoid-responsive elements of the mouse mammary tumor virus promoter. This cell line therefore expresses β-galactosidase only when biologically active 11β-hydroxy glucocorticosteroids are present. The experiments in Fig. 10 demonstrate that although 11β-hydroxy glucocorticosteroids directly drive gene expression, 11-keto glucocorticosteroids are unable to do so unless the cells are concomitantly stimulated by IL-1β. This effect is mediated by 11β-OHSD activity, because it can be abolished with GA in a dose dependent fashion (Fig. 10 b). Furthermore, this effect is specific for 11-keto glucocorticosteroids as cortexolone, a steroid without a functional group at position 11, displays an 11β-OHSD– and cytokine–independent constitutive activity, albeit weak (Fig. 10 a) The relevance of the conversion of cortisone to cortisol was furthermore shown when these two endogenous glucocorticosteroids are present in the low physiological concentration range using Kiki cells (data not shown).

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