(Journal of Leukocyte Biology. 2002;71:9-15.)
© 2002
by Society for Leukocyte Biology
Molecular mechanisms of glucocorticoid antiproliferative effects: antagonism of transcription factor activity by glucocorticoid receptor
Wassim Y. Almawi* and
Ohannes K. Melemedjian
* Department of Medical Biochemistry, Arabian Gulf University, Manama, Bahrain; and
Department of Biology, American University of Beirut, Lebanon
Correspondence: Dr. Wassim Y. Almawi, Department of Medical Biochemistry, College of Medicine & Medical Sciences, Arabian Gulf University, P.O. Box 22979, Manama, Bahrain. E-mail:
wassim{at}agu.edu.bh
 |
ABSTRACT
|
|---|
Glucocorticoids (GCs) exert their anti-inflammatory and
immunosuppressive effects by inhibiting the expression of cytokines and
adhesion molecules. The molecular basis of GC action lies in their
capacity to diffuse through the cell membrane and bind their cytosolic
GC receptor (GR), which subsequently undergoes nuclear translocation
and modulates transcriptional activation through association with
promoter elements, GC response elements (GRE). GR also antagonized the
activity of transcription factors, including NF-
B, NF-AT, and AP-1,
through direct and indirect mechanisms. GCs induced the gene
transcription and protein synthesis of the NF-B inhibitor, IB.
Activated GR antagonized transcription factor activity through
protein:protein interaction. This involved complexing with and
inhibition of transcription factor binding to DNA (simple model),
association with factor bound at its DNA site (composite
model), and/or through interaction of GRE-bound GR with
DNA-bound transcription factor (transmodulation model). Finally, GR
competed with transcription factors for nuclear coactivators
(competition model), including CBP and p300. Remarkably, GR did not
affect the assembly of the preinitiation complex but acted proximally
in inhibiting transcription factor activity and thus transcriptional
initiation.
Key Words: GRE • NF-B • NF-AT • AP-1 • transactivation • transrepression
|
INTRODUCTION
|
|---|
Although glucocorticoids (GCs) are successfully used as potent
immunosuppressive and antiproliferative drugs in treating disorders of
heightened immunity [1
], the molecular mechanism
underlying their effects remains not completely understood. It is well
appreciated that their mode of action is multifactorial, and evidence
of blockade of T-cell immunity at multiple stages by GCs is documented
[1
]. The most significant mechanism of action of GCs
lies in their capacity to block cytokine production [1
,
2
] and for some cytokines, signaling through their
high-affinity receptor complex [3
, 4
].
Originally, it was postulated that this inhibition required a
prerequisite, direct interaction of the activated GC-GC receptor (GR)
complex with DNA sites compatible with the GC response element (GRE)
motif. These sites are located in variable copy numbers and at variable
distances from the TATA box in the promoter region of GC-responsive
genes including cytokine genes. Recent evidence suggested that GCs
modulate transcription through antagonism of transcription factors
required to drive optimal cytokine transcription, including activated
protein-1 (AP-1) complex, NF-AT, and nuclear factor-B
(NF-B). This review focuses on the effect of GCs on
transcription-factor activity. For discussion about other aspects of
GC-antiproliferative effects, the reader is referred to reviews
published elsewhere [1
, 5
].
|
MODE OF ACTION OF GCs
|
|---|
Signaling through the antigen-specific T-cell receptor (TcR)/CD3
complex (signal 1) in conjunction with noncognate costimulatory
signals, including CTLA-4 and its related homologue CD28, and
cytokine receptors (signal 2) results in elevation of intracellular
calcium and the induction of calmodulin-regulated kinases, which
include the serine-threonine phosphatase calcineurin [6
]
and activation and translocation of protein kinase C (PKC) from
cytosolic to membrane-bound compartments where it expresses its
enzymatically active conformation (Fig. 1
). This, in turn, induced the activation and nuclear translocation
of NF-AT (induced by calcineurin) and NF-B (stimulated by PKC and
other signaling pathways), where they bind the interleukin (IL)-2
enhancer and stimulate IL-2 transcription [7
] (Fig. 1)
.
An orderly expression of cytokine genes and their high-affinity
receptors ensues, followed by induction of T-cell proliferation
[8
].
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Figure 1. T-cell activation cascade. T-cell activation through the multimeric
T-cell receptor-CD3 complex results in the activation of several
intracellular signaling pathways leading to phosphorylation or
dephosphorylation of cytoplasmic target molecules. These converge at
provision and nuclear translocation of transcription factors NF-B,
NF-AT, and the AP-1 complex, which subsequently bind their specific
upstream DNA sites, hence facilitating RNA polymerase II-directed
activity.
|
|
GCs antiproliferative effect is largely the result of inhibition of
cytokine expression. GCs inhibited the expression of IL-1
[9
], IL-2 [10
, 11
], IL-3
[12
], IL-4 [13
], IL-5 [2
],
IL-6 [9
], IL-8 [14
], IL-11
[15
], IL-12 [16
, 17
], IL-16
[18
], interferon-
(IFN-) [19
],
tumor necrosis factor-
(TNF-) [20
], and the
colony-stimulating factors (CSF), macrophage (M)-CSF
[21
], granulocyte (G)-CSF [22
], CSF-1
[23
], and granulocyte-macrophage (GM)-CSF
[14
]. Inhibition of cytokine expression was specific for
the GCs because non-GC steroids failed to affect cytokine synthesis
[24
] or T-cell proliferation [25
] and as
the GR antagonist, RU-486 abrogated GC effects [4
,
11
, 16
]. Inhibition of cytokine expression
by GCs involved transcriptional and posttranscriptional events (see
below) and resulted in a significant reduction in cytokine secretion
and a profound inhibition of T-cell-effector function. Furthermore,
recombinant cytokines abrogated GC effects, including apoptosis
[26
], inhibition of cytokine expression
[15
], and suppression of T-cell proliferation
[10
]. Kinetic differences exist between different GCs in
inhibiting cytokine expression and/or T-cell activation, depending on
the GC itself, stimulus used, and activation status
[25
].
|
REPRESSION OF CYTOKINE GENE EXPRESSION BY GC DIRECT
MECHANISMS
|
|---|
Because of their lipophylic nature and low molecular weight, GCs
passively diffuse through the plasma membrane where they bind their
intracellular GR, which functions as a ligand-activated, dual
transcription factor. Depending on the target gene, hormone-activated
GRs may stimulate (transactivation) or inhibit (transrepression) gene
transcription. The former is exemplified by the demonstrated capacity
of GCs to stimulate the production of the NF-B inhibitor, IB
[27
, 28
], and the latter is
exemplified by the demonstrated effect of GCs in suppressing the
expression of IL-2 and other cytokine genes [1
].
In the cytoplasm, GRs exist as an inactive complex with two molecules
of heat-shock protein (HSP-90) and other cytosolic proteins
[29
]. Upon binding its cognate ligand (GCs), GR
undergoes conformational changes, dissociates from HSP-90 binding, and
subsequently translocates to the nucleus where it transiently
associates with HSP-56. GR, in turn, dissociates from HSP-56 and binds
as a dimer to conserved palindromic DNA sequences, the GREs, which
comprise two boxes spaced by three variable nucleotides
(GGTACAnnnTGTTCT), each box binding one of the two GR zinc fingers
[30
]. GREs are located in variable copy numbers and are
found at variable distances from the TATA box in the promoter region of
GC responsive genes, including cytokine genes.
The GR, a member of the steroid superfamily (which includes steroid,
thyroid hormone, vitamin D, and retinoic acid receptors
[31
]), consists of three domains: a hormone-binding
domain, a highly conserved DNA-binding domain, and an N-terminal region
[31
]. An intact GRE site [32
] and DNA
binding domain within the GR [33
] are required for
efficient transcriptional modulation by GCs. Binding of activated GRs
complex to GRE-DNA elements results in downstream inhibition of
cytokine gene expression in a cis-acting (steric hindrance)
[34
] or, alternatively, trans-acting fashion, the latter
involving induction of the synthesis of specific inhibitor(s).
According to the former, GR-GRE binding is viewed as that of a masking
effect, where GR binds to sites overlapping the binding sites of basal
[35
] and induced [36
] transcription
factors, resulting in steric interference with the binding of
transcription/enhancing factors (NF-B, NF-AT) to their putative DNA
sites. The latter involves expression of a specific GC-induced
inhibitor of T-cell activation [37
], including the
NF-B antagonist IB [27
]. It should be noted here
that although evidence supporting both possibilities is documented,
conclusions drawn must be viewed in the context of the cell type and
gene studied.
|
INDIRECT MECHANISMS: ANTAGONISM OF TRANSCRIPTION FACTORS
|
|---|
Although the GR-GRE interaction model provided for a framework to
elucidate the molecular mechanism of GC modulation of gene activation,
recent evidence demonstrated that GCs acted transcriptionally by
antagonizing transcription factor activation or function. This was
evidenced by the demonstrated capacity of GRs to repress transcription
of cytokine genes through interference with the nuclear translocation
and/or function of the transcription factors AP-1 (dimer of c-Fos and
c-Jun) [2
, 38
], NF-B [34
,
39
, 40
], and NF-AT [13
,
33
, 41
]. Reduction in transcription factor
availability and function subsequently translated into reduction and
eventually cessation of transcription in target genes. It is noteworthy
that GR did not interfere with the assembly of the preinitiation
complex (including association of RNA polymerase II with TFII complex
of nuclear proteins), thereby localizing its effect at DNA sites
upstream of the TATA box [42
]. Several mechanisms were
postulated for GC effects, including induction of production of NF-B
inhibitor, IB [27
, 28
, 43
];
protein:protein interaction, where GR prevented transcription-factor
binding to DNA sites [44
, 45
], repressed
the activity of the transcription factor without affecting its binding
onto DNA [34
, 42
], or associated with the
factor, thereby becoming functionally (repressive) active; and
competition with transcription factor for nuclear coactivators
[46
, 47
]. Elucidation of the exact
mechanism of action of the GCs and the scope of interaction of the
activated GR with AP-1, NF-B, NF-AT, and other transcription factors
are of paramount importance toward development of a more
efficacious anti-inflammatory and immunosuppressive regimen.
|
INDUCTION OF IB SYNTHESIS
|
|---|
NF-B, a member of the mammalian rel gene family, which
comprised p105/p50, p100/p52, p65 (RelA), RelB, and others
[48
], is a heterodimer of p65 (RelA) and p50 and in the
inactivated state is sequestered in the cytoplasm through the ankyrin
repeats of its specific inhibitor, IB (Fig. 2
). IB, a member of a large family of inhibitory molecules that
comprised IB, IBß, IB
, and IB
[49
], masked the nuclear localization signal of NF-B,
resulting in its retention in the cytoplasm. Activation by
extracellular signals supposedly induced the phosphorylation and
ubiquitinylation of IB by specific IB kinases (IKK and
IKKß), leading to its rapid proteolytic degradation and thus the
release of NF-B [49
] (Fig. 2)
. NF-B then undergoes
nuclear translocation and binds its decameric DNA response element as a
homo- or heterodimer comprising p50 and p65 (RelA) subunits, thus
stimulating the transcription of NF-B-regulated genes
[48
, 49
], including cytokine and IB
genes [28
, 50
]. Persistent NF-B
activation, in turn, leads to increased IB synthesis and sequesters
cytosolic NF-B, thereby attenuating its activity [48
,
50
].
Several studies documented the capacity of GCs to induce IB
synthesis [27
, 28
]. GC treatment of phorbol
ester 12-O-tetradecanoylphorbol 13-acetate (TPA)-stimulated
Jurkat cells [27
], TNF-stimulated HeLa cells
[28
], vascular epithelial cells of Crohn’s disease
patients [43
], lipopolysaccharide (LPS)-stimulated
macrophages [20
], and brain cells [51
]
resulted in a concentration-dependent induction of IB synthesis.
According to these studies, GC treatment induced IB synthesis
(assessed by gel shift and nuclear run-on transcription assays) without
affecting its phosphorylation and subsequent degradation
[28
]. This constituted a negative feedback loop, whereby
IB binds to and sequesters NF-B in the cytosol and prevents it
from translocating to the nucleus [27
, 28
].
It was even proposed that IB acted at the level of nucleus, binding
and removing NF-B from binding B sites [27
,
28
], although the universality of this finding remains to
be determined.
Several reports disputed induction of IB synthesis as the mechanism
by which GCs repressed gene activation, which was based along several
lines of reasoning. First, it was based on the finding that in many
cell types, GC treatment did not stimulate [52
] or
actually decreased IB synthesis, as was shown for TNF--activated
endothelial cells [34
] and IL-1ß-stimulated epithelial
cells [45
]. GR mutants, which did not enhance IB
synthesis, repressed NF-B activity [40
]. Conversely,
induction of IB synthesis by synthetic GC analogues failed to
repress NF-B activity [40
]. Furthermore, GC-mediated
down-regulation of NF-B was described to be independent of IB
induction [39
, 40
, 53
],
because despite clear induction of IB synthesis by GCs, increased
IB synthesis did not [34
, 39
], or only
partially affected [20
], GC anti-inflammatory and
immunosuppressive effects and because GC effects were resistant to
cycloheximide treatment [34
]. This effectively argued
against induction of de novo IB synthesis or a GC-mediated
stabilization of cytosolic NF-B association with IB
[28
] as potential mechanisms by which GCs repress
transcriptional of cytokine genes.
This indicated that GC induction of IB synthesis and thus antagonism
of NF-B activity is an independent event [53
,
54
] or is cell-type specific [39
,
55
]. However, the latter is questioned, because
contradicting effects of GCs on IB synthesis were observed in the
same tissue and cell types. This was exemplified by the demonstrated
capacity of GCs according to some studies to induce IB synthesis in
brain cells [51
] and in L929 cells [55
]
but in sharp disagreement with other studies, which showed that GCs did
not affect IB levels in brain cells [54
] or in L929
cells [34
]. This prompted the speculation that GC
effects on IB synthesis and subsequently on NF-B synthesis may be
highly cell-specific [39
] or a result of specific
activation signals, and this questioned whether stimulation of IB
synthesis by GCs is even required or sufficient to repress NF-B
activity [40
].
|
PROTEIN:PROTEIN INTERACTION MODEL
|
|---|
A second mechanism by which GCs interacted with and antagonized
transcription factors involved a protein:protein cross-talk between GR
and transcription factors, including NF-AT, NF-B, and AP-1.
According to this model, proposed and increasingly being adopted by
several investigators, the GC antiproliferative effect is viewed as the
result of binding GR to a critical site within the transcription factor
prior to DNA binding (simple model) or following association with the
DNA-binding site of the transcription factor (composite model).
Although direct association of the GR with DNA, for example, through
binding negative GREs, was found not to be obligatory, it was not ruled
out completely. Protein:protein interaction between hormone-activated
GR and transcription factor resulted in interference with the
functional capacity of the transcription factor to stimulate
transcription.
|
THE "SIMPLE" MODEL
|
|---|
The simple model postulates that GR binds the
transcription factor, thereby forming a complex that does not bind DNA
(Fig. 3
). Evidence supporting the simple model was illustrated by the capacity
of GRs to bind to NF-AT [13
], NF-B [34
,
52
, 56
], and AP-1 [56
,
57
], thereby abolishing their capacity to bind DNA. In
exerting its effect, GR did not alter the nuclear translocation
[13
, 56
] or inhibit the synthesis of the
transcription factor [45
, 52
] but acted by
interfering with DNA binding through reciprocal masking of a specific
domain within the GR and the transcription factor (Fig. 3)
[38
]. This did not result in a competitive displacement
of transcription factor bound to DNA but was associated with antagonism
of binding [56
, 58
], evidenced by the
coimmunoprecipitation of GR and nuclear transcription factor
[13
, 44
] and by the reversal of the GC
effect by overexpression of transcription factor [44
],
although the universality of the latter conclusion could not be
confirmed. From suppression of a key signaling pathway involved in
transcription-factor activation, the capacity of the GR to inhibit
transcription-factor binding may have, in principle, exemplified a key
mediator of AP-1 activation [59
] or possibly as a
consequence of earlier antagonism of other transcription factors
[13
], evidenced by the demonstrated capacity of the GCs
to antagonize AP-1 binding through inhibition of c-Jun
NH2-terminal kinase (JNK).
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Figure 3. The "simple model" of protein:protein interaction. According to the
simple model, the hormone-activated GR did not affect the availability
or translocation of transcription factors (exemplified by NF-AT and
NF-B) but rather acted more distally in binding to the transcription
factor in the nucleus and/or cytosol, thereby forming a complex, which
failed to bind to DNA.
|
|
|
THE "COMPOSITE" MODEL
|
|---|
GR antagonized transcription-factor activity through
direct association with the factor without altering its DNA-binding
capability in a mechanism involving specific domains within the
transcription factor and GR. Accordingly, GR exerted its effect, not by
binding DNA or dissociating the transcription factor from DNA binding
[42
, 60
] but by associating with the factor
bound at its putative DNA site, thereby repressing its activity
[34
]. This was evidenced by the capacity of GR to
associate with the transactivating domain of the p65 (RelA) subunit of
NF-B [39
, 42
], which, in turn,
destabilized the interaction of basal transcription factors (TFIID)
with the TATA-binding domain (TBD). In addition to NF-B, GR also
inhibited AP-1 activity without altering the binding of AP-1 (Fos-Jun)
or itself binding to DNA [61
], as evidenced by the
capacity of GR mutants lacking the DNA-binding domain to bind to and
inhibit AP-1 activity [57
, 62
].
Collectively, this indicated that GR acted by forming a complex with
the transcription factor at the binding site of the latter, which, in
turn, attenuates and eventually terminates transcription (Fig. 4
). However, it remains to be seen whether the association of GR with the
transcription factor is sufficient to repress the transcriptional
activity of the latter or, in addition, requires the participation of a
corepressor as was suggested (Fig. 4)
[42
].
|
TRANSMODULATION MODEL
|
|---|
The transmodulation model postulates that interaction of
GRE-bound GR with DNA-bound transcription factor, which occurred
through a direct protein:protein binding, conferred a functional
attribute on GR and resulted in profound inhibition of transcription.
This facilitated direction of ligand-activated GR to its DNA sites
(GREs) [63
], stabilized the interaction of GR with
GRE-like DNA sites, or induced conformational changes in the topology
of DNA, which prevented initiation of proper transcription
[64
]. In support of this scheme were the findings that
AP-1 [41
, 65
, 66
], NF-AT
[13
, 33
, 41
], and ANF-1 and
ANF-2 [66
] facilitated transcriptional repression by GR.
It is noteworthy that GCs did not block the expression of NF-B,
AP-1, AP-3, Oct-1, and NF-AT [13
, 33
,
67
], and evidence of the formation of a complex of these
factors with GR (assessed by double immunoprecipitation) was shown.
Correct spacing between GRE and transcription factor binding sites was
necessary for GR to exert its effect. Interaction of ligand-bound GR
with AP-1, where GRE sites were positioned within a few bases from the
AP-1-binding site, resulted in repression of AP-1-driven activity
[64
]. This did not result from occupancy of the AP-1
site or from inhibition of AP-1 binding, because both factors were
shown to be clearly bound to their DNA sites, but rather involved a
direct protein:protein association of GR with c-Fos and thus repression
of AP-1 activity [64
]. It was interesting to note that
composition of AP-1 influenced GR activity according to this model,
because Jun-Fos heterodimers, but not Jun-Jun homodimers, associated
with GR [68
] and because c-Fos (but not c-Jun) induced
the expression of GR [69
] and associated with it
[64
, 70
]. Collectively, this suggested that
the association of transcription factors with GR, coupled with the
close proximity of their DNA-binding sites to GRE sites, prevented
correct assembly of the preinitiation complex and hence initiation of
proper transcription.
|
COMPETITION MODEL
|
|---|
Insofar as coactivator proteins, including CREB-binding
protein (CBP), p300, steroid receptor coactivator (SRC)-1, and histone
acetyltransferase (HAT), were described to stimulate the activity of
transcription factors, including AP-1 and NF-B [71
],
and as GRs were shown to antagonize transcription factors, it was
suggested that GRs acted, at least in part, by competing with nuclear
transcription factors for nuclear coactivators (Fig. 5
) [47
, 72
]. In support of this were the
findings that CBP augmented GR-suppressive effects [73
],
enhanced the association of GR with CBP, and hence suppressed
NF-B activity [46
, 74
], and as
overexpression of CBP, abrogated GR-mediated repression of NF-B
activity [46
]. GCs down-regulated mRNA and protein
accumulation of SRC-1, a key "adaptor" coactivator, thereby
providing for an autoregulatory loop of GC action [75
].
Insofar as coactivators, including SRC-1 [46
,
76
] and CBP [72
], were described as an
integral link between basal transcription factors and other
transcription factors, including GR and NF-B [72
,
76
], competition for a limited amount of nuclear
coactivators between GR and other induced transcription factors, at
least in part, antagonized transcription factors (Fig. 5)
.
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Figure 5. The "competition model". Coactivator proteins, by associating with
transcription factors (TF) bound at their specific DNA sites
(TF-binding sites) and the preinitiation complex of basal TFs and RNA
polymerase II, facilitate TF effects, thereby promoting transcription.
GR, by binding to the nuclear coactivator, competes with TF for the
coactivator, thereby breaking the link between TF and the preinitiation
complex, thus repressing transcription.
|
|
Other studies argued against competition for nuclear
coactivator(s) as a mechanism by which GR antagonized transcription
factor. For example, GR interacted directly with AP-1
[39
] and NF-B [39
], independently of
CBP levels in the cell. Increased AP-1 and NF-B binding was
associated with overall reduced CREB binding [56
],
thereby questioning whether reduced CREB and other coactivator function
and GR repression of transcription factors were related. Indeed, the
transactivation and transrepression functions of the GR were shown to
be separate entities [40
, 77
], and the
requirement for direct association with specific AP-1 or NF-B
subunits on overall GR function (activation or repression), without
necessarily involving an adaptor or competing for a nuclear
coactivator, is well-documented [39
, 64
,
78
]. Additional studies are required to confirm or
alternatively rule out competition for nuclear coactivator(s) as a
mechanism by which GRs antagonize transcription factors.
|
ANTAGONISM OF TRANSCRIPTION FACTORS BY
GLUCOCORTICOID-REGULATED GENES
|
|---|
In addition to the above-mentioned mechanisms, recent
studies suggested that GCs exerted their effects, at least in part,
through induction of specific GC-regulated genes, GILZ (GC-induced
leucine zipper) and GITR (GC-induced TNFR family-related)
[79
, 80
]. GILZ, a 137-amino acid
leucine-zipper transcription factor, is expressed constitutively in
normal cells and up-regulated by GCs [79
,
81
]. GILZ supposedly mediated a number of GC effects,
including modulation of activation-induced cell death
[79
, 81
] and antagonism of transcription
factors [82
, 83
]. GILZ was shown to act by
inhibiting NF-B translocation and hence its binding to the IB DNA
site through a protein:protein interaction [83
] and to
interact with c-Fos, thereby inhibiting the translocation of AP-1
(dimer of Fos and Jun) and subsequently its DNA binding
[82
]. Collectively, this suggested that GC antagonism of
NF-B and AP-1 activity results, at least in part, from induction of
GILZ.
|
CONCLUSION
|
|---|
During the last two decades, significant advances have been
made toward understanding the precise mode of action of the GCs, and it
now appears to be multifaceted, affecting transcriptional and
posttranscriptional events. In view of the cooperation between
transcription factors in driving optimal transcriptional activation,
exemplified by the obligate induction of AP-1 on subsequent NF-AT
activation, it remains to be determined whether the GC effect on
antagonizing a transcription factor is a direct event or,
alternatively, a consequence of an earlier antagonism of another factor
in the activation cascade [13
]. The many conclusions
drawn from the literature indicate that GCs most likely affect several
transcriptional events, because a single mechanism could not apply to
all cell types and stimulation conditions. A thorough understanding of
the mode of action of the GCs is of paramount importance in better
management of GC toxicity and in the development of a future
immunosuppressive regimen.
Received October 2, 2001;
accepted October 15, 2001.
|
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ABSTRACT
INTRODUCTION
