11β-Hydroxysteroid dehydrogenase type 1—A role in inflammation?

doi:10.1016/j.mce.2005.11.036

Molecular and Cellular Endocrinology

Volume 248, Issues 1–2, 27 March 2006, Pages 3-8

https://doi.org/10.1016/j.mce.2005.11.036 Get rights and content

Abstract

Glucocorticoids are widely used for their potent anti-inflammatory effects. Endogenous glucocorticoids are immunomodulatory and shape both adaptive and innate immune responses. Over the past decade, it has become apparent that an important level of control over endogenous glucocorticoid action is exerted by the 11β-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme, 11β-HSD1, reduces inert glucocorticoids into active forms, thereby increasing intracellular ligand availability to receptors. Although 11β-HSD1 activity has been shown to play an important role in the metabolic actions of glucocorticoids, its role in the immune response has, until recently, remained unclear. Here we review recent evidence pertaining to the role of 11β-HSD1 in the inflammatory response.

Section snippets

Perspective

Glucocorticoids exert potent immunomodulatory effects. At pharmacological levels they are powerful immunosuppressive and anti-inflammatory agents. Clinically, they are widely prescribed to treat inflammation, where often they are the most effective therapy and their utility is limited only by the side effects of long term treatment. The first use of glucocorticoids to treat inflammation in humans was in the late 1940s, by Philip Hench, who in collaboration with Edward Kendall, successfully used

The inflammatory response as an innate response to injury or infection

The inflammatory response, part of the innate immune system, is a first line host defence mechanism that, upon injury, protects against invading pathogens and repairs damaged tissue. The classic signs of inflammation include redness, swelling, heat and pain and result from the release of proinflammatory mediators (e.g. tumour necrosis factor-α; TNF-α) and increased vasodilation and capillary permeability, promoting migration of leukocytes into injured tissues. Activated neutrophil granulocytes

Glucocorticoids suppress the initiation of the inflammatory response

It has been hypothesised that endogenous glucocorticoids provide a “brake” during the initial inflammatory response, to prevent its potentially lethal overshoot (Munck et al., 1984). Support for this view has come from experiments in adrenalectomised rats, in which glucocorticoid treatment is essential to survive challenge with horse serum (Dougherty and Schneebeli, 1955), bacterial lipopolysaccharide (LPS) or tumour necrosis factor-α (TNF-α) (Bertini et al., 1988). However, the view that

11β-HSD1

The enzymatic conversion of cortisone to cortisol by 11β-HSD was described by Amelung et al. (1953), shortly after the award of the 1950 Nobel Prize to Hench. However, it was almost 40 years later that it became clear that there are two enzymes responsible for the interconversion of cortisone and cortisol; 11β-HSD1 which predominantly reactivates and 11β-HSD2, which inactivates glucocorticoids in vivo (reviewed in Seckl and Walker (2001); Tomlinson and Stewart (2001) and elsewhere in this

Future prospects

Macrophages play an essential role in the innate immune system. However, activated macrophages are also central to the pathogenesis of human diseases, including chronic inflammatory conditions and atherogenesis. Given the well known adverse cardiometabolic effects of glucocorticoids and the expression of 11β-HSD1 in macrophages, there is clear potential for macrophage 11β-HSD1 to influence atherogenesis (reviewed by Theringer, this volume).

Elucidation of the transcriptional regulation of

Acknowledgements

Work in the authors’ laboratories is funded by The Wellcome Trust, The National Kidney Research Fund and The Medical Research Council. JSG was supported by a 4 year Ph.D. award from the Wellcome Trust. We thank members of the Centre for Inflammation Research and the Endocrinology Unit for many stimulating discussions.

References (65)

T. Cai et al.
Induction of 11β-hydroxysteroid dehydrogenase type 1 but not 2 in human aortic smooth muscle cells by inflammatory stimuli
J. Steroid. Biochem. Mol. Biol.
(2001)
G. Charriere et al.
Preadipocyte conversion to macrophage. Evidence of plasticity
J. Biol. Chem.
(2003)
X.N. Chen et al.
Impaired generation of bone marrow B lymphocytes in mice deficient in C/EBP-β
Blood
(1997)
L. Freeman et al.
Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells
Blood
(2005)
M.C. Gingras et al.
Differential expression of multiple unexpected genes during U937 cell and macrophage differentiation detected by suppressive subtractive hybridization
Exp. Hematol.
(2000)
C. Haslett et al.
Apoptosis (programmed cell death) and functional changes in aging neutrophils. Modulation by inflammatory mediators
Chest
(1991)
A. Klein et al.
A difference between human B and T lymphocytes regarding their capacity to metabolize cortisol
J. Steroid. Biochem.
(1980)
D. Mason
Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease
Immunol. Today
(1991)
B.S. McEwen et al.
The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions
Brain Res. Rev.
(1997)
N.M. Morton et al.
Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11β-hydroxysteroid dehydrogenase type 1 null mice
J. Biol. Chem.
(2001)

A. Munck et al.

The ups and downs of glucocorticoid physiology. Permissive and suppressive effects revisited

Mol. Cell Endocrinol.

(1992)

V. Poli

The role of C/EBP isoforms in the control of inflammatory and native immunity functions

J. Biol. Chem.

(1998)

M.H. Sieweke et al.

A transcription factor party during blood cell differentiation

Curr. Opin. Genet. Dev.

(1998)

S. Tavor et al.

Macrophage functional maturation and cytokine production are impaired in C/EBP epsilon-deficient mice

Blood

(2002)

J.W. Tomlinson et al.

Cortisol metabolism and the role of 11β-hydroxysteroid dehydrogenase

Best Pract. Res. Clin. Endocrinol. Metab.

(2001)

L.J.S. Williams et al.

C/EBP regulates hepatic transcription of 11β-hydroxysteroid dehydrogenase type 1; a novel mechanism for cross talk between the C/EBP and glucocorticoid signalling pathways

J. Biol. Chem.

(2000)

D. Amelung et al.

Conversion of cortisone to compound F

J. Clin. Endocrinol. Metab.

(1953)

J.D. Ashwell et al.

Glucocorticoids in T cell development and function

Ann. Rev. Immunol.

(2000)

P.J. Barnes

Anti-inflammatory actions of glucocorticoids: molecular mechanisms

Clin. Sci. (Lond.)

(1998)

M.L. Berliner et al.

Interconversion of cortisol and cortisone by normal and leukemic murine lymphocytes

Acta Unio. Int. Contra. Cancrum.

(1964)

R. Bertini et al.

Adrenalectomy sensitizes mice to the lethal effects of interleukin-1 and tumor necrosis factor

J. Exp. Med.

(1988)

M. Botto et al.

Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies

Nat. Genet.

(1998)

Bruley, C., Lyons, V., Worsley, A.G.F., Wilde, M.D., Darlington, G.D., Morton, N.M., Seckl, J.R., Chapman, K.E. A novel...

M.S. Cooper et al.

Modulation of 11β-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation

J. Bone. Miner. Res.

(2001)

T.F. Dougherty et al.

The use of steroids as anti-inflammatory agents

Ann. N.Y. Acad. Sci.

(1955)

G. Escher et al.

Tumor necrosis factor-α and interleukin-1β enhance the cortisone/cortisol shuttle

J. Exp. Med.

(1997)

V.A. Fadok et al.

Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-α, PGE2, and PAF

J. Clin. Invest.

(1998)

R.S.H. Finney et al.

The anti-inflammatory activity of glycyrretinic acid and derivatives

J. Pharm. Pharmacol.

(1958)

K.M. Giles et al.

Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation, and high levels of active Rac

J. Immunol.

(2001)

Gilmour, J.S., 2003. Glucocorticoids, 11β-hydroxysteroid dehydrogenases and macrophage function. Ph.D. Thesis....

Gilmour, J.S., Cailhier, J.-F., Man, T.Y., Coutinho, A.E., Clay, M., Thomas, G., Harris, H.J., Mullins, J.J., Seckl,...

C. Haslett

Granulocyte apoptosis and its role in the resolution and control of lung inflammation

Am. J. Respir. Crit. Care Med.

(1999)

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As extracts contain a mixture of compounds, later work focused on investigating inhibitory activities of individual steroidal derivatives that were found in urine or plasma samples. Some GALF compounds can also inhibit 11β-HSD1 oxoreductase activity [12], thereby likely affecting the regulation of cardio-metabolic processes, neurological activity, behavior and the immune system [18,19]. This review will focus on endogenous steroidal metabolites as potential GALFs, although other endogenous non-steroidal compounds inhibiting 11β-HSD dehydrogenase likely also exist.
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Expression of 11beta-hydroxysteroid-dehydrogenase type 2 in human thymus
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11beta-hydroxysteroid-dehydrogenase type 2 (11β-HSD2) is a high affinity dehydrogenase which rapidly inactivates physiologically-active glucocorticoids to protect key tissues. 11β-HSD2 expression has been described in peripheral cells of the innate and the adaptive immune system as well as in murine thymus. In absence of knowledge of 11β-HSD2 expression in human thymus, the study aimed to localize 11β-HSD2 in human thymic tissue.
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Ligand-receptor interaction between triterpenoids and the 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) enzyme predicts their toxic effects against tumorigenic r/m HM-SFME-1 cells
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Increased 11βHSD1 and decreased 11βHSD2 expressions up-regulated CORT (39). 11βHSD1 acts as an oxoreductase converting 11-dehydrocorticosterone to CORT, whereas 11βHSD2 is a dehydrogenase that inactivates CORT (40), suggesting that increased activity of 11βHSD1 and/or decreased activity of 11βHSD2 up-regulate CORT. GA is a well known specific inhibitor of 11βHSD1 and 11βHSD2 (41).
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This finding contrasts with findings in rats [57], where negligible expression was seen. However, the fact that leucocytes, including macrophages and lymphocytes [26], express this enzyme may account for the positive result from splenic tissue. Nonetheless, although these results are interesting, they are preliminary in nature, and a more detailed study that involves protein and enzyme function in a wider range of tissues is now advisable.
The enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD-1) is expressed in a number of tissues in rodents and humans and is responsible for the reactivation of inert cortisone into cortisol. Its gene expression and activity are increased in white adipose tissue (WAT) from obese humans and may contribute to the adverse metabolic consequences of obesity and the metabolic syndrome. The extent to which 11β-HSD-1 contributes to adipose tissue function in dogs is unknown; the aim of the present study was to examine 11β-HSD-1 gene expression and its regulation by proinflammatory and anti-inflammatory agents in canine adipocytes. Real-time PCR was used to examine the expression of 11β-HSD-1 in canine adipose tissue and canine adipocytes differentiated in culture. The mRNA encoding 11β-HSD-1 was identified in all the major WAT depots in dogs and also in liver, kidney, and spleen. Quantification by real-time PCR showed that 11β-HSD-1 mRNA was least in perirenal and falciform depots and greatest in subcutaneous, omental, and gonadal depots. Greater expression was seen in the omental depot in female than in male dogs (P = 0.05). Gene expression for 11β-HSD-1 was also seen in adipocytes, from both subcutaneous and visceral depots, differentiated in culture; expression was evident throughout differentiation but was generally greatest in preadipocytes and during early differentiation, declining as cells progressed to maturity. The inflammatory mediators lipopolysaccharide and tumor necrosis factor α had a main stimulatory effect on 11β-HSD-1 gene expression in canine subcutaneous adipocytes, but IL-6 had no significant effect. Treatment with dexamethasone resulted in a significant time- and dose-dependent increase in 11β-HSD-1 gene expression, with greatest effects seen at 24 h (2nM: approximately 4-fold; 20nM: approximately 14-fold; P = 0.010 for both). When subcutaneous adipocytes were treated with the peroxisome proliferator activated receptor γ agonist rosiglitazone, similar dose- and time-dependent effects were noted. However, no effects were seen when adipocytes from the gonadal WAT depot were treated with rosiglitazone. The induction of 11β-HSD-1 expression, by the pro-inflammatory cytokine tumor necrosis factor α and by lipopolysaccharide may have implications for the pathogenesis of obesity and its associated diseases in the dog.
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11β-Hydroxysteroid dehydrogenase type 1—A role in inflammation?

Abstract

Section snippets

Perspective

The inflammatory response as an innate response to injury or infection

Glucocorticoids suppress the initiation of the inflammatory response

11β-HSD1

Future prospects

Acknowledgements

J. Steroid. Biochem. Mol. Biol.

J. Biol. Chem.

Blood

Blood

Exp. Hematol.

Chest

J. Steroid. Biochem.

Immunol. Today

Brain Res. Rev.

J. Biol. Chem.

Mol. Cell Endocrinol.

J. Biol. Chem.

Curr. Opin. Genet. Dev.

Blood

Best Pract. Res. Clin. Endocrinol. Metab.

J. Biol. Chem.

Conversion of cortisone to compound F

J. Clin. Endocrinol. Metab.

Glucocorticoids in T cell development and function

Ann. Rev. Immunol.

Anti-inflammatory actions of glucocorticoids: molecular mechanisms

Clin. Sci. (Lond.)

Interconversion of cortisol and cortisone by normal and leukemic murine lymphocytes

Acta Unio. Int. Contra. Cancrum.

Adrenalectomy sensitizes mice to the lethal effects of interleukin-1 and tumor necrosis factor

J. Exp. Med.

Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies

Nat. Genet.

Modulation of 11β-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation

J. Bone. Miner. Res.

The use of steroids as anti-inflammatory agents

Ann. N.Y. Acad. Sci.

Tumor necrosis factor-α and interleukin-1β enhance the cortisone/cortisol shuttle

J. Exp. Med.

Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-α, PGE2, and PAF

J. Clin. Invest.

The anti-inflammatory activity of glycyrretinic acid and derivatives

J. Pharm. Pharmacol.

Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation, and high levels of active Rac

J. Immunol.

Granulocyte apoptosis and its role in the resolution and control of lung inflammation

Am. J. Respir. Crit. Care Med.