Molecular and Cellular Endocrinology 248 (2006) 3–8

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

Karen E. Chapman a,∗ , James S. Gilmour a,b , Agnes E. Coutinho a,b ,
John S. Savill b , Jonathan R. Seckl a
a Endocrinology Unit, Centre for Cardiovascular Sciences, The Queen’s Medical Research Institute, University of Edinburgh,
47 Little France Crescent, Edinburgh EH16 4TJ, UK
b MRC Centre for Inflammation Research, The Queen’s Medical Research Institute,

University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK

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 11␤-hydroxysteroid dehydrogenase enzymes. The type 1 enzyme, 11␤-HSD1, reduces inert glucocorticoids
into active forms, thereby increasing intracellular ligand availability to receptors. Although 11␤-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 11␤-HSD1 in the inflammatory response.
© 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Glucocorticoid; 11␤-hydroxysteroid dehydrogenase; Steroid metabolism; Macrophage; Inflammation

1. Perspective coids, those that express 11␤-HSD1 effectively get a “double

whammy” from circulating active glucocorticoids as well as
Glucocorticoids exert potent immunomodulatory effects. At from the local reactivation of intrinsically inert glucocorticoids.
pharmacological levels they are powerful immunosuppressive This provides a mechanism to locally amplify glucocorticoid
and anti-inflammatory agents. Clinically, they are widely pre- levels, thus targeting their effects to where they are most needed.
scribed to treat inflammation, where often they are the most Here, we review recent data demonstrating expression of 11␤-
effective therapy and their utility is limited only by the side HSD1 in leukocytes and its potential anti-inflammatory role.
effects of long term treatment. The first use of glucocorticoids
to treat inflammation in humans was in the late 1940s, by Philip
2. Inflammation and its resolution
Hench, who in collaboration with Edward Kendall, success-
fully used cortisone to treat rheumatoid arthritis, for which
2.1. The inflammatory response as an innate response to
they were awarded a Nobel Prize in 1950 (Hench, 1950). Of
injury or infection
course, to be effective, the intrinsically inert cortisone must
first be converted to the active glucocorticoid, cortisol, by the
The inflammatory response, part of the innate immune sys-
intracellular action of 11␤-hydroxysteroid dehydrogenase type
tem, is a first line host defence mechanism that, upon injury,
1 (11␤-HSD1). Paradoxically, glycyrrhetinic acid, a deriva-
protects against invading pathogens and repairs damaged tissue.
tive of liquorice which inhibits 11␤-HSD, also shows anti-
The classic signs of inflammation include redness, swelling,
inflammatory activity (Finney and Somers, 1958), presumably
heat and pain and result from the release of proinflammatory
through delaying the clearance of cortisol (or corticosterone)
mediators (e.g. tumour necrosis factor-␣; TNF-␣) and increased
from blood by renal 11␤-HSD2. However, whereas cells that
vasodilation and capillary permeability, promoting migration of
express 11␤-HSD2 are resistant to the effects of glucocorti-
leukocytes into injured tissues. Activated neutrophil granulo-
cytes are generally the first cells attracted to the site of inflam-
Abbreviations: 11␤-HSD, 11␤-hydroxysteroid dehydrogenase
mation, rapidly followed by monocyte emigration from blood
∗ Corresponding author. Tel.: +44 131 242 6736. vessels and their subsequent maturation into macrophages. Once
E-mail address: Karen.Chapman@ed.ac.uk (K.E. Chapman). at the inflamed site, neutrophils undergo constitutive apoptosis,

0303-7207/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.mce.2005.11.036
4 K.E. Chapman et al. / Molecular and Cellular Endocrinology 248 (2006) 3–8
functionally isolating them from the inflammatory environment
by loss of stimulated chemotaxis, phagocytosis, degranulation
and respiratory burst (Haslett et al., 1991; Whyte et al., 1993),
whilst at the same time, facilitating safe removal of their poten-
tially histotoxic contents by macrophages (Savill et al., 2002).
2.2. The importance of resolution of inflammation
The inflammatory response is largely beneficial, and acute
inflammation normally quickly resolves. However, it may
become persistent, leading to chronic disease and irreversible
organ damage. The hallmark of chronic inflammation is the sus-
tained presence and accumulation of activated macrophages,
which continue to release proinflammatory mediators and are
thus responsible for much of the tissue damage. Although many
of the initial events in an inflammatory response have been char-
acterised, the mechanisms responsible for its resolution remain
incompletely understood. It is likely that chronic inflammation,
such as occurs during rheumatoid arthritis or asthma, results
from an imbalance between the initial proinflammatory events
needed for adequate protection against infection and the mecha-
nisms that terminate the inflammatory response, restoring home-
ostasis (Haslett, 1999).
2.3. The role of the macrophage
Crucial to the rapid and safe resolution of acute inflamma-
tion is macrophage clearance of leukocytes undergoing apop-
tosis at sites of inflammation (Botto et al., 1998; Savill et al.,
2002; Taylor et al., 2000). Unlike phagocytosis of necrotic
cells or invading pathogens, the ingestion of apoptotic cells by
phagocytes does not evoke a proinflammatory response (Fadok
et al., 1998; Meagher et al., 1992). In contrast, active anti-
inflammatory and immunosuppressive responses are elicited
following phagocytosis of apoptotic cells (Voll et al., 1997). If
the removal of apoptotic granulocytes is impaired, they rapidly
undergo secondary necrosis, provoking release of proinflamma-
tory mediators from the phagocyte and prolonging the inflam-
matory response (Botto et al., 1998; Taylor et al., 2000). The
macrophage is the principal phagocyte. However, under cer-
tain circumstances, other cell types, e.g. glomerular mesangial
cells (Hughes et al., 1997) are able to phagocytose apoptotic
cells. Although blood monocytes can bind apoptotic cells, they
lack phagocytic capacity (Newman et al., 1982; Savill et al.,
1989) and little is known of the mechanisms that operate early
in the acute inflammatory response to promote the acquisition
by maturing monocytes of phagocytic capacity for apoptotic
leukocytes. However, recent data suggest this can be profoundly
influenced by glucocorticoids.
3. Glucocorticoids and the inflammatory response
3.1. 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 adrenalec-
tomised rats, in which glucocorticoid treatment is essential to
survive challenge with horse serum (Dougherty and Schneebeli,
1955), bacterial lipopolysaccharide (LPS) or tumour necrosis
factor-␣ (TNF-␣) (Bertini et al., 1988). However, the view that
glucocorticoid actions are solely immunosuppressive is over-
simplistic; physiological levels exert permissive and stimula-
tory effects as well as suppressive and are better described as
immunomodulatory (reviewed in McEwen et al. (1997); Munck
et al. (1984); Yeager et al. (2004)). Glucocorticoids potently alter
leukocyte distribution/trafficking, alter cellular differentiation
programmes and alter transcription of numerous genes in the
glucocorticoid sensitive leukocytes; monocytes/macrophages,
neutrophils and granulocytes (Ashwell et al., 2000; McEwen
et al., 1997). Notably, glucocorticoids repress transcription
of genes encoding proinflammatory mediators – particularly
cytokines and their receptors – whilst increasing transcription
of anti-inflammatory proteins including IL-10 and IL-1 receptor
antagonist (Barnes, 1998).
3.2. Glucocorticoids promote the resolution of
inflammation
The mechanisms by which glucocorticoids promote reso-
lution of inflammation have received less attention than those
associated with suppression of the initial inflammatory response.
Recent work from Edinburgh is elucidating some of the mech-
anisms that may account for the efficacy of glucocorticoids in
resolving inflammation. Synthetic glucocorticoids increase the
capacity of individual macrophages to ingest multiple apoptotic
cells (Liu et al., 1999). Moreover, exposure of blood mono-
cytes to glucocorticoids, at the beginning of their maturation
into macrophages, reprogrammes their differentiation into a
highly phagocytic “anti-inflammatory” macrophage phenotype
(Giles et al., 2001; Heasman et al., 2003), a phenomenon that
can be modulated by local cytokine environment (Heasman
et al., 2003). In addition, glucocorticoids modify granulocyte
apoptosis—accelerating eosinophil apoptosis whilst delaying
neutrophil apoptosis (Meagher et al., 1996). Thus, the pro-
resolution effects of glucocorticoids upon inflammation are
complex—mediated by several cell types and dependent upon
the local (cytokine) environment.
3.3. Influence of endogenous glucocorticoids and HPA
activity upon the inflammatory response
It has been proposed that the effects of glucocorticoids
follow a bell-shaped dose response curve, with permissive
and stimulatory effects exerted at physiological concentra-
tions and suppressive effects at high pharmacological con-
centrations (Munck and Naray-Fejes-Toth, 1992; Sapolsky et
al., 2000). Thus, whilst pharmacological levels of glucocorti-
coids are immunosuppressive, the effects of physiological levels
are immunomodulatory. Considerable evidence implicates the
hypothalamic–pituitary–adrenal (HPA) axis, governing the out-
put of glucocorticoid from the adrenal gland, in susceptibility to
 K.E. Chapman et al. / Molecular and Cellular Endocrinology 248 (2006) 3–8
inflammatory and autoimmune disease (Sternberg, 2001). Fis-
cher 344/N rats, which have larger adrenals and mount a greater
corticosterone response to stress than the genetically related
Lewis/N rat are resistant to the development of arthritis induced
by streptococcal cell wall, whereas Lewis/N rats are susceptible,
a difference that can be reversed by manipulation of gluco-
corticoid action in these strains (Sternberg et al., 1992). Sim-
ilarly, development of experimental allergic encephalomyelitis
in rats is strongly influenced by endogenous glucocorticoids
(Mason, 1991). Importantly, neonatal exposure of rats to bacte-
rial LPS, which programmes lifelong changes in HPA activity,
also strongly influences susceptibility to inflammatory disease in
adulthood (Shanks et al., 2000). Increased glucocorticoid (HPA
axis) activity shifts the balance of an immune response from a
type 1-associated (proinflammatory) cytokine profile to a type
2-associated (anti-inflammatory) cytokine profile (McEwen et
al., 1997). Whilst this is beneficial during normal progression
of an inflammatory/immune response, if the balance is altered
in favour of the type 2 response prematurely, then a suffi-
ciently robust response may not be mounted in the early stages
of the inflammatory response, allowing progression to chronic
inflammation. Thus, initially following injury, it is important to
contain adventitious infections and a strong type 1 response is
required for this. However, an unregulated response is poten-
tially lethal. Endogenous glucocorticoids maintain the balance
between the early control and elimination of infection follow-
ing injury and overshoot leading to tissue damage. Perhaps the
ability to switch from this early phase of infection control, to the
later pro-resolution phase of tissue repair is similarly influenced
by endogenous glucocorticoids.
4. 11␤-HSD1
The enzymatic conversion of cortisone to cortisol by 11␤-
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; 11␤-HSD1 which predominantly reactivates and 11␤-
HSD2, which inactivates glucocorticoids in vivo (reviewed in
Seckl and Walker (2001); Tomlinson and Stewart (2001) and
elsewhere in this volume). Whilst the importance of the liver to
the regeneration of blood cortisol from cortisone (or corticos-
terone from 11-dehydrocorticosterone in rodents) has long been
known, the role of 11␤-HSD1 in the local regeneration of glu-
cocorticoids, within cells, from inert substrate has only recently
been fully recognised. The 11␤-HSDs play a dual role in glu-
cocorticoid action. Firstly, adrenal secretion of glucocorticoids
into the circulation is influenced by the balance between hep-
atic 11␤-HSD1 (reactivation) and renal 11␤-HSD2 (clearance)
activities and secondly, within specific cell types, the enzymes
gate glucocorticoid access to glucocorticoid receptors. Thus,
cells which express 11␤-HSD2 are glucocorticoid resistant,
whereas cells that express 11␤-HSD1 boost the glucocorticoid
levels which access receptors, through intracellular regener-
ation of the ample circulating inert 11keto-steroid substrate,
levels of which depend primarily on the action of renal 11␤-
5
HSD2. Intracellular glucocorticoid concentrations can there-
fore differ from plasma glucocorticoid levels and depend upon
the 11␤-HSD isozyme expressed. The many and varied roles
of 11␤-HSD1 are now being elucidated—particularly impor-
tant in this has been the generation of mice deficient in 11␤-
HSD1 (Kotelevtsev et al., 1997). These mice cannot reduce
11-dehydrocorticosterone to corticosterone (Kotelevtsev et al.,
1997) and are protected against the adverse metabolic effects of
glucocorticoids (Kotelevtsev et al., 1997; Morton et al., 2001;
Morton et al., 2004) and glucocorticoid-associated cognitive
decline (Yau et al., 2001). Although they have normal amounts
of adipose tissue, at least on a low fat diet (Morton et al., 2004),
they lack bone marrow adipocytes (Justesen et al., 2004); the
functional relevance of this is currently unclear. However, until
very recently, immune function, and particularly the inflamma-
tory response, had not been investigated in these mice.
4.1. 11β-HSD1 is expressed in immune cells, including
macrophages
Previous studies with the liquorice-derived 11␤-HSD
inhibitor glycyrrhetinic acid suggested a role for 11␤-HSDs in
immunity (Finney and Somers, 1958; Hennebold et al., 1997;
Pompei et al., 1979), although as mentioned above, the anti-
viral and anti-inflammatory effects are probably attributable to
11␤-HSD2 inhibition (Horigome et al., 1999), rather than 11␤-
HSD1 inhibition. Older studies on 11␤-HSD function in lym-
phocytes measured 11␤-HSD dehydrogenase activity or failed
to discriminate between the isozymes (Berliner and Dougherty,
1964; Klein et al., 1980)—it remains unclear whether these
data pertain to 11␤-HSD1 or 11␤-HSD2 activity. More recently,
11␤-HSD1 expression has been described in immune cells.
In 2000, 11␤-HSD1 was identified in a subtractive hybridisa-
tion screen as induced during the differentiation of a human
myelomonocytic cell line (Gingras and Margolin, 2000). Sub-
sequent work by Thieringer showed that although 11␤-HSD1
is not expressed in circulating human monocytes, it is induced
upon differentiation to macrophages (Thieringer et al., 2001).
Furthermore, 11␤-HSD1 expression could be induced in mono-
cytes by the “type 2” response cytokines IL-4 and IL-13, an
effect that was abrogated in the presence of proinflammatory
IFN-␥ (Thieringer et al., 2001). Somewhat confusingly, in the
same study, LPS was shown to increase 11␤-HSD1 expres-
sion in the macrophage-like cell line, THP-1 (Thieringer et al.,
2001). We have confirmed expression of 11␤-HSD1 in human
monocyte-derived macrophages (Gilmour, 2003) and have also
demonstrated expression of 11␤-HSD1, but not 11␤-HSD2,
in mouse macrophages (Gilmour et al., 2005). Our own data
in human cells suggest that IL-4 may accelerate macrophage
differentiation, rather than directly induce 11␤-HSD1 activity
(Gilmour, 2003). Recently, 11␤-HSD1 expression and activ-
ity have been described in mouse and human dendritic cells
(Freeman et al., 2005; Zhang et al., 2005) as well as mouse T and
B lymphocytes (Zhang et al., 2005). Interestingly, in immature
human dendritic cells activated by proinflammatory mediators,
including TNF-␣ or LPS (innate immune activating signals),
expression of 11␤-HSD1 was maintained, whereas maturation
6 K.E. Chapman et al. / Molecular and Cellular Endocrinology 248 (2006) 3–8
induced by CD40 ligation (a signal associated with adaptive
immune activation) markedly reduced expression (Freeman et
al., 2005). Thus, 11␤-HSD1 expression in monocyte-derived
cells is exquisitely sensitive to differentiation state and activating
signals. We have recently used a mouse model of acute inflam-
mation, thioglycollate-induced sterile peritonitis, to show a rapid
increase (within 3 h) in 11␤-HSD1 activity in cells elicited to the
peritoneum following thioglycollate injection (Gilmour et al.,
2005), consistent with induction by proinflammatory mediators.
Levels remained high in peritoneal macrophages until resolu-
tion, when activity returned to that of resident (unstimulated)
macrophages (Gilmour et al., 2005).
4.2. Regulation of 11β-HSD1 by inflammatory mediators
Numerous lines of evidence show that proinflammatory
mediators, especially TNF-␣ and IL-1, are potent inducers
of 11␤-HSD1 expression and activity in a variety of cell
types. Mesangial cells, which share some characteristics with
macrophages, showed increased activity of 11␤-HSD1 with the
proinflammatory cytokines, TNF-␣ and IL-1␤ (Escher et al.,
1997). Both TNF-␣ and IL-1␤ increased 11␤-HSD1 expression
in primary cultures of human preadipocytes (Tomlinson et al.,
2001), a cell type with a lineage closely related to macrophages
(Charriere et al., 2003). During ovulation, a process akin to an
inflammatory response with “injury” (ovulation) and “resolu-
tion” (luteinising) phases, there is a reciprocal switch in expres-
sion of 11␤-HSD1 and 11␤-HSD2 in granulosa cells. Prior to
ovulation, 11␤-HSD2 is expressed, rendering granulosa cells
glucocorticoid insensitive. By contrast, uniquely 11␤-HSD1 is
expressed in luteinised granulosa cells, where expression is
further increased by IL-1␤, enhancing local production of gluco-
corticoid (Tetsuka et al., 1999, 1997). Ovarian surface epithelial
cells also express 11␤-HSD1, and again, expression is increased
by IL-1 (Yong et al., 2002). Thus, induction of 11␤-HSD1
expression and activity by proinflammatory-like mediators in
the ovary may serve to minimise inflammatory tissue damage
following ovulatory rupture. A similar reciprocal regulation of
11␤-HSD1 and 2 has been described in human MG-63 osteosar-
coma cells (Cooper et al., 2001) and human aortic smooth
muscle cells (Cai et al., 2001). In both cases, IL-1␤ or TNF-
␣ potently down-regulated 11␤-HSD2 expression, concomitant
with up-regulation of 11␤-HSD1 (Cai et al., 2001; Cooper et
al., 2001). Thus a consistent pattern emerges, with proinflam-
matory mediators, particularly TNF-␣ and IL-1␤, increasing
11␤-HSD1 expression, promoting local glucocorticoid avail-
ability and hence local anti-inflammatory action.
4.3. 11β-HSD1−/− mice show a delay in the acquisition of
macrophage phagocytic capacity
In vitro, corticosterone similarly promotes phagocytosis of
apoptotic neutrophils by bone marrow derived macrophages,
irrespective of whether the macrophages originate from
11␤-HSD1−/− or control mice (Gilmour et al., 2005). 11-
Dehydrocorticosterone was equally effective in promoting
phagocytosis by control macrophages, but was completely
ineffective in 11␤-HSD1−/− macrophages (Gilmour et al.,
2005). Crucially, during sterile peritonitis, the acquisition of
macrophage phagocytic capacity was delayed in 11␤-HSD1-
deficient mice compared to control mice, and these mice showed
delayed clearance of apoptotic neutrophils as experimental peri-
tonitis progressed (Gilmour et al., 2005). Based on these data
and the evidence pertaining to its regulation by proinflammatory
mediators, we have proposed that 11␤-HSD1 is a component of
mechanisms that are engaged early in the acute inflammatory
response in order to promote later resolution (Gilmour et al.,
2005).
A similar role for 11␤-HSD1 in shaping the immune response
has previously been proposed (Rook et al., 2000). Initially,
following M. tuberculosis infection in mice, type 1 (IFN-␥,
IL-2) and proinflammatory (IL-1, TNF-␣) cytokines predom-
inate, associated with an 11␤-HSD equilibrium in lung favour-
ing reductase. This enhances local glucocorticoid availability,
polarising the subsequent response towards type 2 (IL-4), and
decreased IL-1 and TNF-␣ expression. The latter phase of type
2 cytokine production was associated with a switch in the 11␤-
HSD equilibrium to increased dehydrogenase. Although it is
not yet clear to what extent these shifts of the 11␤-HSD equi-
librium reflect alterations in local expression of 11␤-HSD1,
11␤-HSD2 or both, it is nevertheless apparent that local (11␤-
HSD-mediated) alterations in glucocorticoid availability may be
actively shaping the immune/inflammatory response as it pro-
gresses. Further characterisation of the immune/inflammatory
response in 11␤-HSD1−/− mice will illuminate the role of 11␤-
HSD1.
5. 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 inflamma-
tory conditions and atherogenesis. Given the well known adverse
cardiometabolic effects of glucocorticoids and the expression
of 11␤-HSD1 in macrophages, there is clear potential for
macrophage 11␤-HSD1 to influence atherogenesis (reviewed
by Theringer, this volume).
Elucidation of the transcriptional regulation of 11␤-HSD1 in
immune cells, particularly macrophages, will provide a greater
understanding of the part the enzyme plays in the inflamma-
tory response. The C/EBP family of transcription factors exert
a major control over 11␤-HSD1 transcription (Williams et al.,
2000) and family members play key roles in leukocyte differen-
tiation programmes (Chen et al., 1997; Sieweke and Graf, 1998;
Tavor et al., 2002) as well as the inflammatory response (Poli,
1998). Whether they are as much a requirement for 11␤-HSD1
transcription in leukocytes as they are in metabolic tissues (e.g.
liver and adipose tissue) remains to be determined. Our recent
data has shown that in some tissues 11␤-HSD1 transcription ini-
tiates from a novel upstream promoter (Bruley et al., submitted
for publication); again, future work will establish whether this
is of relevance in immune cells. The benefits of glucocorti-
coid therapy in arthritis and other inflammatory conditions is
 K.E. Chapman et al. / Molecular and Cellular Endocrinology 248 (2006) 3–8
well accepted. A clearer understanding of the role and regu-
lation of 11␤-HSD1 in macrophages and other leukocytes will
have important therapeutic implications for rheumatoid arthritis,
atherogenesis and other inflammatory diseases.
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.
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