European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Perspective

Anti-inflammatory glucocorticoids: Changing concepts

Robert Newton n
Department of Cell Biology and Anatomy, Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University
of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1

art ic l e i nf o a b s t r a c t

Article history: Despite being the most effective anti-inflammatory treatment for chronic inflammatory diseases, the
Received 13 March 2013 mechanisms by which glucocorticoids (corticosteroids) effect repression of inflammatory gene expres-
Received in revised form sion remain incompletely understood. Direct interaction of the glucocorticoid receptor (NR3C1) with
13 May 2013
inflammatory transcription factors to repress transcriptional activity, i.e. transrepression, represents one
Accepted 29 May 2013
mechanism of action. However, transcriptional activation, or transactivation, by NR3C1 also represents an
important mechanism of glucocorticoid action. Glucocorticoids rapidly and profoundly increase expres-
Keywords: sion of multiple genes, many with properties consistent with the repression of inflammatory gene
Glucocorticoid expression. For example: the dual specificity phosphatase, DUSP1, reduces activation of mitogen-
Corticosteroid
activated protein kinases; glucocorticoid-induced leucine zipper (TSC22D3) represses nuclear factor-κB
Transactivation
(NF-κB) and activator protein 1 (AP-1) transcriptional responses; inhibitor of κBα (NFKBIA) inhibits NF-
Transrepression
Inflammation κB; tristraprolin (ZFP36) destabilises and translationally represses inflammatory mRNAs; CDKN1C, a cell
Anti-inflammatory cycle regulator, may attenuate JUN N-terminal kinase signalling; and regulator of G-protein signalling 2
(RGS2), by reducing signalling from Gαq-linked G protein-coupled receptors (GPCRs), is bronchoprotec-
tive. While glucocorticoid-dependent transrepression can co-exist with transactivation, transactivation
may account for the greatest level and most potent repression of inflammatory genes. Equally, NR3C1
transactivation is enhanced by β2-adrenoceptor agonists and may explain the enhanced clinical efficacy
of β2-adrenoceptor/glucocorticoid combination therapies in asthma and chronic obstructive pulmonary
disease. Finally, NR3C1 transactivation is reduced by inflammatory stimuli, including respiratory
syncytial virus and human rhinovirus. This provides an explanation for glucocorticoid resistance.
Continuing efforts to understand roles for glucocorticoid-dependent transactivation will provide
opportunities to improve glucocorticoid therapies.
& 2013 Published by Elsevier B.V.

1. Introduction therapy (Newton et al., 2010b; Barnes, 2013). While respiratory

Glucocorticoids (corticosteroids) acting on the glucocorticoid
receptor (NR3C1) (See Table 1 for list of gene symbols and
function), a ligand-activated transcription factor, represent the
most effective anti-inflammatory drugs currently available for
the treatment of chronic inflammation (Barnes, 2006). Topical
glucocorticoids are central to the management of multiple inflam-
matory conditions. Thus inhaled glucocorticoids, referred to clini-
cally as inhaled corticosteroids, are used in asthma, and, typically
as a combination with long-acting β2-adrenoceptor agonists, in
chronic obstructive pulmonary disease. Despite this, many indivi-
duals respond poorly to glucocorticoid therapy. In chronic obstruc-
tive pulmonary disease, severe asthma, asthmatics who smoke,
and viral exacerbations of both diseases, inhaled glucocorticoids
are of limited effect, necessitating, high-doses, or often oral
diseases account for the greatest patient numbers using oral
glucocorticoids, inflammatory conditions of the skin, subcuta-
neous and musculoskeletal tissues, nervous and digestive systems
are also significant (van Staa et al., 2000). However, glucocorti-
coids do not cure chronic disease, leading to long-term treatments
and side-effects including osteoporosis, tissue wasting, cataracts,
diabetes and hypothalamic-pituitary-adrenal axis suppression.
Since, these are not off-target responses, but reflect NR3C1
physiology, the identification of anti-inflammatory NR3C1 ligands,
which avoid resistance, and/or show reduced side-effect profiles,
are goals of the pharmaceutical sector. Success requires a clear
understanding of how glucocorticoids repress inflammation.
2. Repression of gene expression drives anti-inflammatory
effectiveness

n
Tel.: +1 403 210 3938; fax: +1 403 210 7944. Of the many glucocorticoid-dependent responses, down-
E-mail address: rnewton@ucalgary.ca regulation of inflammatory gene expression is most critical for

0014-2999/$ - see front matter & 2013 Published by Elsevier B.V.

http://dx.doi.org/10.1016/j.ejphar.2013.05.035

Please cite this article as: Newton, R., Anti-inflammatory glucocorticoids: Changing concepts. Eur J Pharmacol (2013), http://dx.doi.org/
10.1016/j.ejphar.2013.05.035i
2 R. Newton / European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

Fig. 1. Schematic showing the inhibition of inflammatory gene expression by glucocorticoids. (A) An inflammatory cytokine binding to its receptor activates kinase cascades.
IκB kinase 2 (IKK2) activation leads to the phosphorylation of the inhibitor of κBα (IκBα) (NFKBIA), which leads to its rapid degradation and the release of active NF-κB
(p50/p65). This translocates to the nucleus to activate inflammatory gene transcription. Activation of mitogen-activated protein kinase kinase kinase (MAP3Ks) leads to
activation of the downstream MAPKs. MAPKs can enhance the transcriptional activity of NF-κB and AP-1, and also cause mRNA stabilisation and translational activation of
inflammatory genes. While glucocorticoids may induce the expression of hundreds of effector genes, effects of selected glucocorticoid-inducible genes may include: dual-
specificity phosphase 1 (DUSP1) (also known as MKP-1) inhibits MAPKs to prevent transcription, mRNA stability and translation; IκBα/NFKBIA inhibits NF-κB; Glucocorticoid-
induced leucine zipper (GILZ/TCS22D3) can inhibit both NF-κB and AP-1; Tristetraprolin (TTP/ZFP36) promotes deadenylation, degradation and translational silencing of
AU-rich element (ARE)-containing inflammatory mRNAs; CDKN1C is a cell-cycle kinase inhibitor and a potential inhibitor of JNK, which may prevent proliferative responses
and the induction of pro-inflammatory genes respectively. (B) Activation of the NF-κB signal transduction cascade by IKK2 leads to rapid degradation of IκBα/NFKBIA and
release of active NF-κB (p50/p65). Binding of glucocorticoid (yellow) to the cytoplasmic glucocorticoid receptor (GR) (NR3C1) causes translocation of the receptor to the
nucleus where it can inhibit transcriptional activation by NF-κB. This may occur by up-regulating the expression of IκBα/NFKBIA (or other proteins indicated in (A)), reducing
the expression of p50/p105 (NFKB1), or via transrepression, i.e. direct binding to NF-κB to recruit histone deacetylase 2 (HDAC2). (C) Ligand-activated GR/NR3C1 can inhibit
AP-1-dependent transcription via the mechanisms indicated in (A) as well as by reducing the expression of the composite AP-1 factors, here FOS and JUN, or by via
transrepression, i.e. direct binding to AP-1 (FOS/JUN heterodimer) to recruit HDAC2 and attenuate transcription.

anti-inflammatory effect (Barnes, 2006; De Bosscher et al., 2003).
Reduced expression of chemokines, cytokines, inflammatory
enzymes, adhesion molecules and other inflammatory proteins
in, on or from epithelial, endothelial, smooth muscle, fibroblasts
and other cell types, reduces recruitment, maturation, and/or
survival of inflammatory cells. This lowers the inflammatory cell
burden. Equally, acting on inflammatory cells, glucocorticoids
produce similar repressive effects. However, mechanisms by
which glucocorticoids repress inflammatory gene expression
remain unclear (Clark and Belvisi, 2012). In this respect, inflam-
matory gene expression involves regulated mRNA stabilisation and
translation, in addition to the more readily documented changes in
gene transcription (Fig. 1A). Consequently, repressive mechanisms
that solely address gene transcription can only represent one part
of the picture. Thus, without NR3C1 over-expression, glucocorti-
coids may only partially repress transcription, yet reduce mRNA
stability and translation, which together account for the repression
of inflammatory gene expression (Fig. 1A) (Newton and Holden,
2007; Clark and Belvisi, 2012).
3. Repression of inflammatory gene transcription
by glucocorticoids
That glucocorticoids repress the transcriptional activity of key
inflammatory transcription factors, such as nuclear factor-κB
(NF-κB) and activator protein (AP)-1, makes conceptual sense as
their binding sites are both common in the promoters of inflam-
matory genes and crucial for transcriptional up-regulation (De
Bosscher et al., 2003). Indeed, glucocorticoids can reduce the DNA
binding ability of NF-κB and AP-1 to the their cognate DNA motifs
(Yang-Yen et al., 1990; Mukaida et al., 1994). Such effects may be
partly explained by the glucocorticoid-dependent down-regula-
tion of the constituent transcription factor components, p50/p105
(NFKB1) of NF-κB, or c-Jun (JUN), c-Fos (FOS) and Fra1 (FOSL1) of
AP-1 (Hass et al., 1991; Tacon et al., 2012; Newton et al., 1998), plus
up-regulation of the NF-κB inhibitor, inhibitor of κBα (NFKBIA)
(Scheinman et al., 1995) (Fig. 1B and C). However, many NF-κB-
dependent genes are poorly, or even not, repressed by glucocorti-
coids (King et al., 2013). Furthermore, such genes may play roles in
host defence or the resolution of inflammation, for which there
could be an advantage to being spared the repressive effects of
glucocorticoids (Stellato, 2007; Gilroy et al., 2004). Indeed this
realisation implies a necessarily gene-specific, rather than activa-
tor-specific, aspect to the repressive actions of glucocorticoids.
Furthermore, glucocorticoid-repression of inflammatory gene
expression can be dissociated from up-regulation of NFKBIA and
is not necessarily accompanied by reduced NF-κB or AP-1 DNA
binding (Konig et al., 1992; Newton et al., 1998; Heck et al., 1997).
Thus independent mechanisms of repression must also exist. For
example, NR3C1 may directly bind NF-κB and AP-1, to promote
transcriptional repression i.e. transrepression (Jonat et al., 1990;

Please cite this article as: Newton, R., Anti-inflammatory glucocorticoids: Changing concepts. Eur J Pharmacol (2013), http://dx.doi.org/
10.1016/j.ejphar.2013.05.035i
 R. Newton / European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Ray and Prefontaine, 1994). In this model, occupancy of NF-κB or
AP-1 at their cognate DNA binding motifs leads to the activation of
inflammatory gene transcription, whereas in the presence of GR
tethered to NF-κB or AP-1, there is transrepression (De Bosscher
et al., 2003). While competition between NR3C1 and the inflam-
matory transcription factors for transcriptional co-activator mole-
cule was suggested, this seems unnecessary for repression (De
Bosscher et al., 2001; De Bosscher et al., 2000). Indeed, the
presence of NR3C1 at inflammatory gene promoters is associated
with the recruitment of repressive factors, such as histone deace-
tylase 2, which by deacetylating the promoter region causes
repression (Ito et al., 2000) (Fig. 1A and B).
In addition, NR3C1 may directly bind DNA at negative gluco-
corticoid response elements (GREs) to repress transcription (De
Bosscher et al., 2003). While negative GREs are not generally
thought to apply to inflammatory genes, a novel negative GRE was
recently described in respect of glucocorticoid-dependent repres-
sion of the cytokine, thymic stromal lymphopoietin (TSLP), when
induced with a vitamin D3 analogue (Surjit et al., 2011). In this
case, NR3C1 bound DNA in a head-to-tail fashion (compared with
symmetrically at simple positive GRE sites) (Hudson et al., 2013).
However, significance in the context of inflammatory stimuli is
untested.
4. Repression that is not transrepression
Expression of cytokines, for example granulocyte–macrophage
colony-stimulating factor (CSF2), tumour necrosis factor α (TNF) or
interleukin 1β (IL1B), and inflammatory proteins, such as cycloox-
ygenase 2 (PTGS2), depend on mitogen-activated protein kinases
(MAPKs), in particular p38 MAPK, but also extracellular regulated
kinase (ERK) and JUN N-terminal kinase (JNK), to provide mRNA
stabilisation and translational activation by inflammatory stimuli
(Fig. 1A) (Newton and Holden, 2003; Anderson, 2008; Swantek
et al., 1997). Furthermore, glucocorticoids reduce MAPK activation
(Swantek et al., 1997; Kassel et al., 2001; Lasa et al., 2001), in a
manner that is prevented by transcriptional and translational
inhibitors (Lasa et al., 2001; King et al., 2009a; Newton et al.,
2010a). Likewise, glucocorticoid-dependent repression of multiple
inflammatory genes is prevented by transcriptional and transla-
tional blockers (Newton and Holden, 2007; Clark and Belvisi,
2012). This suggests a requirement for gene expression and
indeed, glucocorticoids strongly induce expression of dual-
specificity phosphatase 1 (DUSP1), also known as MAPK phospha-
tase 1, to reduce MAPK activation (Kassel et al., 2001; Lasa et al.,
2002; Issa et al., 2007; King et al., 2009a; Newton et al., 2010a).
Thus loss of DUSP1 expression attenuates glucocorticoid-
dependent repression of inflammatory gene expression
(Abraham et al., 2006; Issa et al., 2007; Quante et al., 2008)
(Fig. 1A). Likewise, the mRNA destabilising protein, tristetraprolin
(ZFP36), provides feedback control of multiple inflammatory
genes, including TNF, IL1B and CSF2 (Anderson, 2008). Though
primarily induced by inflammatory stimuli (King et al., 2009b),
ZFP36 expression is induced by glucocorticoids to exert repression
(Smoak and Cidlowski, 2006; Ishmael et al., 2008) (Fig. 1A).
5. Repression of inflammatory gene transcription
by NR3C1 transactivation
While direct NR3C1-mediated repression of transcription, i.e.
transrepression, is thought to explain the repression of inflamma-
tory gene transcription (De Bosscher et al., 2003), NF-κB- and
AP-1-dependent transcription can depend on MAPKs (Newton and
Holden, 2003; Newton and Holden, 2007). Thus MAPK inhibitors
Please cite this article as: Newton, R., Anti-inflammatory glucocorticoids: Changing concepts. Eur J Pharmacol (2013), http://dx.doi.org/
10.1016/j.ejphar.2013.05.035i
3
reduce NF-κB-dependent transcription (Vanden Berghe et al.,
1998; Bergmann et al., 1998; Saccani et al., 2002). Equally, MAPK
activation is integral to the expression and transcriptional activa-
tion of AP-1 and glucocorticoid inhibition of JNK represses AP-1
activity (Gonzalez et al., 2000). It is therefore unsurprising that the
induction of DUSP1, to switch off MAPKs, is implicated in the
glucocorticoid-repression of NF-κB and AP-1 (Diefenbacher et al.,
2008; King et al., 2009a; Jang et al., 2007) (Fig. 1A). Additionally,
glucocorticoid-induced leucine zipper (TSC22D3) is profoundly
induced by glucocorticoids in airway epithelial cells (Eddleston
et al., 2007), airways smooth muscle (Kelly et al., 2012), mast cells
(Godot et al., 2006), and T cells (Mittelstadt and Ashwell, 2001),
and can repress both NF-κB and AP-1 (Ayroldi and Riccardi, 2009).
Since TSC22D3 expression is induced in asthmatics taking the
inhaled glucocorticoid, budesonide, a therapeutic role must be
considered (Kelly et al., 2012) (Fig. 1A). Likewise, the cell cycle
inhibitor, CDKN1C, is induced by glucocorticoids in airway epithe-
lial and smooth muscle cells and is reported to inhibit the JNK
MAPK pathway (Chang et al., 2003; Kaur et al., 2008), an effect
that should impact on AP-1 (Fig. 1A). Thus, NR3C1 transactivation
induces the expression of multiple genes that can reduce inflam-
matory gene transcription.
6. Relative roles for transrepression and transactivation
Despite the potential for GR transactivation in reducing inflam-
matory gene expression, the relationship with transrepression is
unclear. This was recently addressed in respect of inflammatory
genes induced by IL1B (King et al., 2013). In these experiments,
cycloheximide, which blocks translation, totally prevented the
dexamethasone-dependent repression of multiple mRNAs, includ-
ing IL8, CSF2 and CXCL1. This implies repressive mechanisms
involving gene expression. Conversely, other mRNAs, for example
TNF or ICAM1, showed dexamethasone-dependent repression that
was unaffected by cycloheximide and therefore conforms to
classical transrepression. Finally, there were mRNAs, for example
PTGS2 and CXCL3, showing both cycloheximide-sensitive and
-insensitive components to the repression by dexamethasone.
Thus glucocorticoids appear to exert repression of inflammatory
genes via both transrepression and transactivation. However, of
potential therapeutic significance was the fact that the inflamma-
tory mRNAs showing cycloheximide-sensitive repression were
significantly more repressed and were more potently repressed
compared to those mRNAs conforming to the classical transrepres-
sion model (King et al., 2013).
7. Consequences for drug development
Current studies provide clear support for glucocorticoid-
dependent repression occurring by transrepression, as well as
via transactivation of repressive genes. Such data have enormous
implications in respect of attempts to improve the therapeutic
ratio of glucocorticoids. Thus, searching for so called “dissociated”
NR3C1 ligands that transrepress, yet show impaired transactiva-
tion, on the basis that this will reduce side effects, were, in
principle, misplaced. However, using functional outputs, such as
NF-κB-, or AP-1-dependent transcription, or the repression of
inflammatory gene expression inherently identifies NR3C1 ligands
that elicit repression, irrespective of mechanism. Thus, apparently
“dissociated” NR3C1 ligands that retain anti-inflammatory/repres-
sive activity are likely to retain the ability to induce expression of
“anti-inflammatory” genes. For example, the anti-inflammatory,
dissociated glucocorticoid, RU24858, represses inflammatory gene
expression in a manner that is prevented by inhibiting gene
4 R. Newton / European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

expression and also induces the expression of genes, for example
DUSP1, to switch off MAPK pathways (Vayssiere et al., 1997;
Chivers et al., 2006; Newton et al., 2010a). Similarly, the repressive
effectiveness of novel NR3C1 ligands correlates with their ability
to induce DUSP1 expression (Joanny et al., 2012). Since DUSP1 is
merely one of many genes showing anti-inflammatory potential,
ongoing functional analyses of glucocorticoid-induced anti-
inflammatory genes will promote the quality of screening strate-
gies for improved NR3C1 ligands.
The predictive value of transactivation as a mechanism of
repression extends to an improved understanding of the clinical
efficacy of inhaled corticosteroid/long-acting β2-adrenoceptor ago-
nist combination therapies in asthma and chronic obstructive
pulmonary disease (Newton et al., 2010b). In both conditions,
such combinations provide superior disease control over that
achievable by inhaled glucocorticoid alone. While glucocorticoids
exert beneficial effects on β2-adrenoceptor signalling and attenu-
ate pro-inflammatory effects of long-acting β2-adrenoceptor ago-
nists (Newton et al., 2010b), it is clear that by activating the cAMP
cascade, β2-adrenoceptor agonsits can synergistically promote
glucocorticoid-dependent transcription to levels that cannot be
achieved by glucocorticoids alone (Kaur et al., 2008). This synergy
extends to genes such as CDKN1C, whereas DUSP1 shows simple
additivity in smooth muscle and epithelial cells (Kaur et al., 2008;
Manetsch et al., 2012). Similarly, regulator of G-protein signalling 2
(RGS2), a bronchoprotective gene that attenuates signalling from
Gαq-coupled receptors, is induced by β2-adrenoceptor agonists in
airways smooth muscle and shows dramatically enhanced and
prolonged expression in the presence of glucocorticoid plus long-
acting β2-adrenoceptor agonists (Holden et al., 2011). Thus NR3C1
transactivation may explain the enhanced clinical benefit of these
therapies, as well as the efficacy of phosphodiesterase 4 inhibitors
administered in the context of a glucocorticoid (Moodley et al.,
2013).
Finally, the hypothesis that NR3C1 transactivation provides
important therapeutic benefits, offers insight as to the mechan-
isms of glucocorticoid resistance. Thus glucocorticoid-induced
transcription, including the expression of real genes, is markedly
attenuated by a variety of inflammatory and remodelling stimuli,
including pro-inflammatory cytokines and mitogens (Rider et al.,
2011; Salem et al., 2012). Indeed, this repressive effect is observed
in response to viruses including respiratory syncytial virus and
human rhinovirus, as well as to the double-stranded RNA, poly(I:C)
(a replicating viral genome mimetic) (Hinzey et al., 2011; Rider
et al., 2013). Since virus infections, in particular human rhinovirus,
are a leading cause of asthma and chronic obstructive pulmonary
disease exacerbations (Barnes, 2013), it is plausible that the down-
regulation of glucocorticoid-induced transcription provides some
explanation for reduced glucocorticoid responsiveness. While
reductions in glucocorticoid-dependent transcription, like the clin-
ical situation, cannot be overcome by increasing the concentration
of glucocorticoid (Rider et al., 2011; Rider et al., 2013), it is likely

Table 1
Gene nomenclature and function.

Official gene symbol Gene name (other common names) Brief function and description
(other common
aliases)

CXCL3 (GRO3, GROg, C-X-C motif chemokine 3 (growth regulated protein 3/ Chemokine. Binds to the CXCR2 receptor which is present on macrophage,
MIP-2b, MIP2B) gamma, macrophage inflammatory protein 2 beta) neutrophils and eosinophils.
CDKN1C (p57Kip2) Cyclin-dependent kinase inhibitor 1C (cyclin-dependent A cell cycle regulator that inhibits cyclin-dependent kinases
kinase inhibitor p57)
CSF2 GMCSF Colony stimulating factor 2 (granulocyte–macrophage Cytokine that regulates the production, differentiation, survival and function of
colony-stimulating factor) granulocytes and macrophage
DUSP1 (MKP-1, MKP1, Dual-specificity phosphatase 1 (MAPK phosphatase 1) Dual-specificity phosphatase that can dephosphorylate and inactivate p38, ERK and
CL100) JNK MAPKs
FOS (C-FOS) FBJ murine osterosarcoma viral oncogene homologue Transcription factor that heterodimerises with members of the JUN family of proteins
to create activator protein (AP)-1
FOSL1 (FRA, FRA1, FOS-like antigen 1 Transcription factor of the FOS family that heterodimerises with members of the JUN
fra-1) family of proteins to create activator protein (AP)-1
ICAM1 Intercellular adhesion molecule 1 Expression on the surface of endothelial and epithelial cells is induced by
inflammatory stimuli. Play a role in transmigration of inflammatory cells
IL1B (IL-1, IL-1beta) Interleukin 1 beta Pro-inflammatory cytokine released by macrophage and other cells. Pleotropic
biological responses
IL8 (CXCL8) Interleukin 8, chemokine (C-X-C motif) ligand 8 C-X-C chemokine that is in particular a chemoattractant for neutrophils. Binds to the
CXCR1 and 2 receptors present on macrophage, neutrophils and eosinophils
NFKBIA (IKBA, MAD-3, Nuclear factor of kappa light polypeptide gene enhancer Cytoplasmic inhibitor of NF-κB that hold NF-κB (p55/p65) inactive in the cytoplasm.
NFKBI) in B-cells inhibitor, alpha (inhibitor of kappa B alpha) Dual phosphorylation on serines 32 and 36 result in ubiquitination and degradation
to release active NF-κB, which translocates to the nucleus
JUN (C-JUN) Jun proto-oncogene Transcription factor activated by the c-Jun N-terminal kinase. Heterodimerises with
FOS family members such as FOS (c-fos) to create activator protein (AP)-1
NFKB1 (p50, p105, Nuclear factor of kappa light polypeptide gene enhancer NFKB1 encodes the p105. This undergoes proteolytic cleavage to produce p50, the
NF-kB1) in B-cells 1 main DNA binding subunit of NF-κB that heterodimerises with RelA (p65)
NR3C1 (GR) Nuclear receptor subfamily 3, group C, member 1 Ligand-activated transcription factor responsive to glucocorticoids. Binding of agonist
(glucocorticoid receptor) ligand result in translocation from the cytoplasm to the nucleus where the
transcription of target genes can be modified
PTGS2 (COX-2, COX2, Prostaglandin G/H synthase 2 (cyclooxygenase 2) Catalyses the formation of prostaglandin H2 from prostaglandin G2. Expression is
PGHS-2) induced by inflammatory stimuli to produce prostaglandins
TSC22D3 (GILZ) TSC22 domain family, member 3 (glucocorticoid- Leucine zipper protein, i.e. a putative transcription factor, that has been shown to
induced leucine zipper) down-regulate the activity of NF-κB and AP-1.
TNF (TNFA, TNF-alpha) Tumour necrosis factor (tumour necrosis factor alpha) Pro-inflammatory cytokine secreted by macrophage and other cells. Pleotropic
biological responses.
TSLP Thymic stromal lymphopoietin Cytokines that acts on myeloid cells to induce the release of chemokines. TSLP is
implicated in Th2 type responses
ZFP36 (TTP) Zinc finger protein 36 (tristetraprolin) mRNA binding protein that binds AUUUA motifs present in many inflammatory gene
mRNAs. Causes mRNA decay and translational suppression

Please cite this article as: Newton, R., Anti-inflammatory glucocorticoids: Changing concepts. Eur J Pharmacol (2013), http://dx.doi.org/
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 R. Newton / European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎
that specific signalling events are responsible for the effect.
This provides a strong rationalisation for testing inhibitors of
signalling pathways as a means of restoring glucocorticoid tran-
scriptional responses in the context of viral infections.
8. Conclusions
It is now very apparent that transcriptional activation by NR3C1
represents an important effector response in eliciting anti-
inflammatory actions. Despite this, a fuller characterisation of
such effects is necessary to more completely understand the
mechanisms underlying anti-inflammatory glucocorticoid action.
Thus, the “transactivation” hypothesis offers attractive explana-
tions for the enhancement of glucocorticoid actions by β2-adreno-
ceptor agonists and for reduced effectiveness in certain situations.
However, it is critical that such new information is carefully
integrated into an overall model that also incorporates direct
transrepression, as well as established effectors, such as annexin
AI (ANXA1) (Perretti and D'acquisto, 2009).
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