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B Activity by Glucocorticoids
Hubrecht Laboratory Netherlands Institute for Developmental Biology 3584 CT Utrecht, The Netherlands
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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B-dependent
gene expression is one of the key characteristics by which
glucocorticoids exert their antiinflammatory and immunosuppressive
effects. In vitro studies have shown protein-protein
interactions between NF-B and the glucocorticoid receptor, possibly
explaining their mutual repression of transcriptional activity.
Furthermore, glucocorticoid-induced transcription of IB
was
presented as a mechanism in mediation of immunosuppression by
glucocorticoids. At present, the relative contribution of each
mechanism has not been investigated. We show that dexamethasone induced
IB gene transcription in human pulmonary epithelial A549 cells.
However, this enhanced IB synthesis did not cause repression of
NF-B DNA-binding activity. In addition, dexamethasone was still
able to inhibit the expression of NF-B target genes
(cyclooxygenase-2, intercellular adhesion molecule-1) in the absence of
protein synthesis. Furthermore, we show that the antihormone RU486 did
not induce IB expression. However, RU486 was still able to
induce, albeit less efficiently, both glucocorticoid- and progesterone
receptor-mediated repression of endogenous NF-B target gene
expression in A549 cells and the breast cancer cell line T47D,
respectively. Taken together, these results indicate that induced
IB expression accounts for only part of the repression of NF-B
activity by glucocorticoids and progestins. In addition,
protein-protein interactions between NF-B and the glucocorticoid or
progesterone receptor, resulting in repression of NF-B activity,
seem also to be involved. We therefore conclude that NF-B activity
is repressed via a dual mechanism involving both protein-protein
interactions and induction of IB. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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B
(3, 4, 5).
The NF-B/Rel family of transcription factors regulates the
expression of many genes involved in immune and inflammatory responses.
NF-B was originally identified as a heterodimer of NF-B1 and RelA
(6), but a variety of other B/Rel homo- and heterodimers have now
been described. NF-B is present in an inactive state in the
cytoplasm, sequestered by an inhibitor protein, designated IB. After
stimulation of the cells, IB becomes phosphorylated, ubiquitinated,
and subsequently degraded (7). As a result, NF-B is free to
translocate to the nucleus and activate transcription of target genes.
In the nucleus, NF-B can also induce the synthesis of IB,
which terminates the NF-B response, explaining its transient nature
(8).
Glucocorticoids were shown to be potent inhibitors of NF-B
activation. In addition, the NF-B subunit, RelA, has been shown to
physically interact with GR in vitro (9, 10, 11, 12) as well as with
other steroid receptors, such as the estrogen receptor (ER; Ref.13),
the progesterone receptor (PR; Ref.14), and the androgen receptor (AR;
Ref.15). Since it has been demonstrated that NF-B was also able to
repress ligand-dependent activation of steroid receptor-regulated
promoters in vitro, a mutually inactive complex formed
either by direct protein-protein interaction of the receptor and RelA
or via a third partner has been proposed (9, 10, 11, 12, 13, 14, 15).
A second independent mechanism through which glucocorticoids could
repress NF-B activity has been described (16, 17). Glucocorticoids
were shown to induce transcription of the IB gene in HeLa cells,
monocytic cells, and T-lymphocytes. This induction resulted in
increased synthesis of IB protein, which is able to interact with
activated NF-B, thereby terminating the NF-B response. However,
Brostjan et al. (18) reported that glucocorticoid-mediated
repression of NF-B activity did not involve induction of IB
synthesis in endothelial cells.
The physiological relevance of both these mechanisms has not been
clearly established, and it remains unclear which pathway represents
the major mechanism. Therefore, we investigated the contribution of
each mechanism to the antiinflammatory and immunosuppressive activity
of glucocorticoids. Here we show that dexamethasone (Dex) induces
expression of IB in human pulmonary epithelial A549 cells.
Furthermore, we show that Dex is able to inhibit the expression of two
endogenous NF-B target genes, cyclooxygenase-2 (COX-2) and
intercellular adhesion molecule-1 (ICAM-1) partially independent of
newly synthesized IB. On the basis of these results, we conclude
that glucocorticoids repress NF-B activity in A549 cells via a dual
mechanism, which involves both protein-protein interaction and
induction of IB.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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B in A549 CellsB synthesis
in monocytic and lymphocytic cells (16, 17), but not in endothelial
cells (18). To determine whether glucocorticoids increased IB
mRNA in human pulmonary epithelial A549 cells, Northern blotting
analysis was performed on mRNA derived from these cells treated with
Dex for increasing periods of time. As shown in Fig. 1
, Dex induced an increase in IB
mRNA in these cells, which peaked by 2–8 h (3- to 4-fold) and remained
elevated to 24 h (2-fold).
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B-Regulated Genes Is Not Only Mediated by
IB InductionB
activity by glucocorticoids, we determined the repression by Dex of
NF-B-regulated genes in the absence of IB protein synthesis.
Treatment of A549 cells with interleukin (IL)-1ß resulted in a 5-fold
increase in IB mRNA expression, and a 3-fold induction was
observed after treatment with Dex. The combination of IL-1ß and Dex
showed a similar induction as IL-1ß treatment alone (Fig. 2A, lanes 1–4). Dex-mediated IB
induction and IB resynthesis after IL-1ß-induced degradation
can be observed for IB protein (Fig. 2B, lanes 1–4), indicating
that IL-1ß and Dex can induce both IB transcription and protein
synthesis in A549 cells. Cycloheximide (CHX), an inhibitor of protein
synthesis, also induced IB mRNA expression (5-fold; Fig. 2A, lane
5), as has been observed for other NF-B target genes,
e.g. ICAM-1 (19). CHX together with IL-1ß superinduced
IB mRNA (29-fold; Fig. 2A, lane 6), whereas CHX in combination
with Dex resulted in a weaker induction (9-fold; Fig. 2A, lane 7). No
resynthesis of IB protein could be observed in the presence
of CHX (Fig. 2B, lanes 6 and 8).
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B target gene expression, COX-2 (20)
and ICAM-1 (21) mRNA expression was investigated. As shown in Fig. 2C
, IL-1ß induced the expression of both COX-2 and ICAM-1, which could be
strongly repressed by Dex (lanes 2 and 4). Interestingly, in the
absence of protein synthesis and IB protein induction, Dex was
still able to repress IL-1ß-induced COX-2 and ICAM-1 expression
(lanes 6 and 8), although the repression was less strong than in the
absence of CHX (Fig. 2C, right panel). This suggests that
induction of IB plays a role, but is obviously not the only
mechanism mediating the repressive effect of Dex.
NF-B DNA-Binding Activity Is Not Inhibited by Dex
It has been shown that Dex-induced IB was able to
inhibit NF-B activity by preventing nuclear translocation and DNA
binding (16, 17). To determine whether Dex-induced IB could block
NF-B DNA-binding activity in A549 cells, the cells were pretreated
with Dex for 15 h and subsequently treated with IL-1ß for 1
h. NF-B binding to the radiolabeled probe containing the human
immunodeficiency virus (HIV) long terminal repeat (LTR) was observed
with nuclear extracts from cells treated with IL-1ß (Fig. 3, lane 3). Pretreatment with Dex did not
result in inhibition of binding (lane 5). The same results were
obtained after pretreatment with Dex for 5 h (data not shown). The
observed binding activity was specific because it could be competed
with a 100-fold excess of unlabeled B probe but not with a mutant
B probe (lanes 6 and 7). The B-binding activity was composed
mostly of NF-B1 and RelA heterodimer (NF-B) as determined by
supershift analysis (lanes 8 and 9). The faster migrating complexes
appeared to contain NF-B1 protein in other combinations.
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B is not
able to prevent nuclear translocation or DNA binding of NF-B,
suggesting a minor contribution of IB in the mechanism of
repression.
Antihormones Repress NF-B Activity without Induction of
IB
We recently showed that the antiglucocorticoid/antiprogestin
RU486 was able to induce PR-mediated repression of RelA activity (14).
To examine the repression of NF-B target genes by RU486-occupied GR,
we transiently transfected COS-1 cells with a reporter construct
containing four NF-B sites from the ICAM-1 promoter. Cotransfection
with expression vector encoding RelA (20 ng) resulted in an induction
of luciferase activity, which could be repressed by cotransfection of
an expression vector for GR (200 ng) and treatment of the cells with
RU486 (Fig. 4A). The repressive activity
of GR was only slightly reduced with an RU486-occupied receptor
(
65% repression) as compared with a receptor occupied with the
agonist Dex (85% repression).
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, cotransfection of an expression vector encoding GR resulted in
a hormone-dependent induction of luciferase activity after treatment of
the cells with Dex (65-fold) and very low induction upon RU486
treatment (3-fold). This indicates that repression by RU486 is not
correlated with transcriptional activation mediated by RU486.
In A549 cells, both Dex and RU486 were able to repress IL-1ß-induced
COX-2 mRNA expression, although the anti-hormone was less efficient
(Fig. 5A, lanes 1–4). As expected, the
antagonist RU486 was unable to induce IB mRNA (Fig. 5A, lane 6)
or IB protein (Fig. 5C, lanes 4 and 6) in these cells, indicating
that IB synthesis is not necessary for repression of NF-B
activity by RU486.
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B target genes in
these cells containing endogenous PR, the same experiment was performed
in T47D cells. Both the progestagen Org2058 and the progesterone
antagonist RU486 were able to repress IL-1ß-induced ICAM-1 expression
(Fig. 5B, lanes 3 and 4). Whereas Org2058 induced IB mRNA
expression, RU486 was unable to induce IB mRNA in these cells
(Fig. 5B, lanes 5 and 6), although a small increase in IB protein
could be observed (Fig. 5D, lanes 4 and 6). The fact that
RU486-occupied receptors are able to repress NF-B target gene
expression in the absence of induced IB expression indicates that
the repression of endogenous NF-B target genes by GR and PR is at
least partially mediated by an IB-independent mechanism. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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B plays a pivotal role in the regulation of a variety of
genes involved in immune and inflammatory responses. Therefore,
inhibition of NF-B activity can account for many of the
immunosuppressive and antiinflammatory activities of glucocorticoids.
In the present study, we show that glucocorticoids can control immune
response and inflammation by repressing NF-B activity via a dual
mechanism.
First, Dex was shown to induce IB mRNA expression in A549 cells,
which has also been reported for HeLa cells, monocytic cells, and T
lymphocytes (16, 17). The fact that this induction occurs in the
presence of CHX suggests that glucocorticoids activate IB gene
transcription directly. For these cells it has been shown that
Dex-induced IB was able to inhibit NF-B activity by preventing
nuclear translocation and DNA binding of NF-B (16, 17). However, in
A549 cells we observed no inhibition of NF-B DNA-binding activity by
Dex, suggesting that in this case the Dex-induced IB was not able
to efficiently sequester NF-B in the cytoplasm and to prevent DNA
binding. Similar results have been described for endothelial cells
(18). Nevertheless, repression of NF-B activity by protein-protein
interaction can occur via tethering of GR to NF-B in its DNA-bound
form, without affecting DNA binding.
Second, we showed that in the absence of IB protein synthesis,
Dex was still able to repress IL-1ß-induced expression of the NF-B
target genes, COX-2 and ICAM-1. The repressive activity of Dex in the
presence of CHX was less strong than in the absence of CHX, providing
evidence for more than one mechanism involved in Dex-mediated
repression of NF-B activity. In contrast to this observation, Auphan
et al. (16) and Scheinman et al. (17) showed that
in the presence of CHX, inhibition of NF-B DNA binding activity
could no longer be observed, suggesting a requirement of IB for
repression of NF-B activity. However, we showed that in A549 cells,
IB was unable to prevent NF-B DNA binding, suggesting that
inhibition of NF-B DNA binding is not essential for repression of
NF-B target genes in these cells.
As we showed previously for the repression of RelA activity by PR
(14), we found that the antiprogestin/antiglucocorticoid RU486 was also
able to induce GR-mediated repression of RelA activity. In addition,
RU486 could repress IL-1ß-induced expression of COX-2 in A549 cells,
albeit less efficiently than the agonist, Dex. Furthermore, RU486 was
able to induce PR-mediated repression of the IL-1ß-induced
expression of the NF-B target gene, ICAM-1, in T47D cells. In
contrast to the agonists, Dex and Org2058, RU486 was not able to induce
IB synthesis in both cell lines. Taken together, these findings
demonstrate that in addition to Dex- and Org2058-induced IB
synthesis, a second mechanism must be involved in the repression of
NF-B activity by both glucocorticoids and progestins. Furthermore,
Dex-mediated repression of NF-B activity has been shown to be
independent of IB synthesis in endothelial cells (18) and in rat
kidney epithelial cells (23), which again suggests that the induction
of IB is not a universal mechanism explaining NF-B repression
by glucocorticoids in all cell types. In addition to the induction of
IkB synthesis, glucocorticoids have been shown to repress
transcription of target genes by transcriptional interference, a
mechanism likely to involve protein-protein interactions between GR and
NF-B (9, 10, 11, 12). In this way, GR can interfere with the transcriptional
activity of NF-B by 1) forming a complex with NF-B and inhibiting
its DNA-binding activity or by 2) forming a complex with NF-B in its
DNA-bound form without affecting DNA binding, or by 3) contacting a
cofactor that is bound to NF-B and thereby inhibiting the
transactivation potential of NF-B. Further experiments will have to
be carried out to determine which of the mechanisms is involved. GR has
been found to associate in vitro with NF-B either in a
manner leading to inhibition of DNA binding (9, 10) or without
affecting DNA binding (18, 21). However, previous reports regarding a
decreased AP-1 DNA-binding activity in the presence of GR in
vitro (24) could not be confirmed by in vivo
footprinting studies (25). Therefore in vivo footprinting
analysis could be used to study NF-B binding to DNA in the presence
of GR. Similar to GR, other steroid receptors, such as ER (13), PR
(14), and AR (15), have also been shown to physically interact with
NF-B in vitro and inhibit its transcriptional activity,
suggesting an important role for protein-protein interactions in
repression of NF-B activity by steroids.
In contrast to the previously described mechanism, which indicates that
inhibition of NF-B activity does not rely on interaction between GR
and NF-B but is predominantly based on induction of IB
expression, we provide evidence that both mechanisms, resulting in
repression of NF-B activity, contribute to the antiinflammatory
action of glucocorticoids. The involvement of both these mechanisms
emphasizes the importance of multiple levels of regulation of NF-B
activity by glucocorticoids in modulation of the antiinflammatory
response. This sustains the possibility of developing ligands that
specifically activate the repression function of GR and that may
therefore be more efficient in the treatment of inflammatory diseases
without undesirable side effects.
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MATERIALS and METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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B was purchased from Upstate Biotechnology Inc. (Lake Placid,
NY). The polyclonal antibody against the N terminus of RelA was from
Santa Cruz Biotechnology (Santa Cruz, CA). Antiserum 2 against NF-B1
was a kind gift of Dr. A. Israël (Paris, France).
Cell Culture
Human pulmonary epithelial A549 cells were obtained from
American Type Culture Collection (ATCC; Rockville, MD). Cells were
cultured in DMEM from Life Technologies Inc. (Gaithersburg, MD),
buffered with bicarbonate, and supplemented with 7.5% FCS from Integro
(Linz, Austria). Monkey COS-1 cells (ATCC) and human breast tumor T47D
cells, originally provided by Dr. R. L. Sutherland (Sydney,
Australia), were cultured in a 1:1 mixture of DMEM and Ham’s F-12
medium (DF; Life Technologies Inc.), buffered with bicarbonate, and
supplemented with 7.5% FCS. Dextran-coated charcoal-FCS was prepared
by treatment of FCS with dextran-coated charcoal to remove steroids, as
described previously (26).
Plasmids and Transient Transfections
The luciferase reporter plasmid (4xNF-B(IC)tkluc)
containing four NF-B sites from the ICAM-1 promoter was
constructed by ligating two copies of the annealed oligonucleotides
(5'-AGCTTATGGAAATTCCGAGATCATGGAAATTCCGAC-3') and
(5'-AGCTGTCGGAATTT-CCATGATCTCGGAATTTCCATA-3'), containing two NF-B
sites from the ICAM-1 promoter and HindIII linkers, into the
HindIII site of ptkluc. The reporter plasmid 2xGREtkluc has
been described elsewhere (27). The CMV4 expression vectors containing
full-length cDNAs encoding human RelA and GR have been described
previously (11). For transient transfections, COS-1 cells were cultured
in 24-well plates and transfected using calcium-phosphate
coprecipitation with 0.4 µg luciferase reporter, 0.6 µg PDMlacZ,
and the indicated amount of expression plasmids. pBluescript was added
to obtain a total amount of 2 µg DNA/well. After 16 h, the
medium was refreshed and hormone was added. Cells were harvested
24 h later and assayed for luciferase activity using the Luclite
luciferase reporter gene assay kit (Packard Instruments, Meriden, CT)
according to the manufacturer’s protocol and the Topcount liquid
scintillation counter (Packard Instruments). Values were corrected
for transfection efficiency by measuring ß-galactosidase
activity (28).
Northern Blotting Analysis
A549 cells were cultured in 10-cm dishes, treated as indicated,
and harvested. T47D cells were cultured in DF+, supplemented with 5%
dextran-coated charcoal-FCS, and treated as A549 cells. Total RNA was
isolated using the acid-phenol method of Chomczynski and Sacchi (29).
Twenty micrograms of RNA were fractionated on a 0.8% agarose gel and
transferred to Hybond C-extra membranes by capillary transfer using
10xstandard sodium citrate (SSC). The blots were baked under vacuum
for 2 h at 80 C. The blots were hybridized to cDNA probes
overnight at 42 C in hybridization buffer. Subsequently, blots were
washed with 2xSSC/0.1%SDS, 1xSSC/0.1%SDS, 0.2xSSC/0.1%SDS, and
0.1xSSC/0.1%SDS when necessary. cDNA probes were labeled with
[32P]dCTP by random priming according to the
manufacturer’s protocol (Amersham Pharmacia Biotech., Rainham, Essex,
UK). As probes for Northern blotting, a 1-kb HindIII
fragment of the IB cDNA, a 1.8-kb XbaI fragment of the
ICAM-1 cDNA, a 1-kb EcoRI/XhoI fragment of the
murine COX-2 cDNA, a kind gift from Dr. H. Herschman, and a 1.4-kb
PstI fragment of the glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) were used.
Western Blotting Analysis
For isolation of whole cell extracts A549 cells were cultured in
5-cm dishes, treated as described, and harvested in buffer containing
50 mM Tris (pH 7.4), 50 mM NaCl, 0.5% nonidet
P-40, 1 mM dithiothreitol, 1 mM
phenylmethylsulfonylfluoride, 1 µg/ml aprotinin, and 1 µg/ml
leupeptin at 4 C. Subsequently, cells were centrifuged for 15 min at 4
C, and protein concentration of the supernatant was determined by the
Bio-Rad (Richmond, CA) protein assay according to the manufacturers
protocol. Twenty five micrograms of extract were separated on SDS-PAGE
gels and transferred to Immobilon (Milipore, MA). For the polyclonal
antibody against IB (Upstate Biotechnology Inc.), all incubations
were carried out according to the manufacturer’s protocol.
Immunoreactive bands were visualized with enhanced chemiluminescence
(ECL) (Amersham).
Electrophoretic mobility shift assay (EMSA)
A549 cells were cultured in 10-cm dishes and pretreated with Dex
(1 µM) for 15 h and with IL-1ß (100 U/ml) for
1 h. Cells were harvested and nuclear extracts were prepared
according to Lee et al. (30). A double-stranded
oligonucleotide containing the B site from the HIV LTR
(5'-agcttcagaGGGGACTTTCCgagagg-3') was labeled with
[32P]dCTP using the Klenow fragment of DNA polymerase I.
Labeled probe was separated from unincorporated nucleotides by gel
filtration on Sephadex G-50 spin columns and eluted overnight from 5%
polyacrylamide gels in 0.5 M
CH3COONH4/1 mM EDTA at 37 C.
Nuclear extracts of A549 cells (10 µg per assay) were incubated with
10.000 cpm of probe (0.1 to 0.5 ng) and 1 µg poly(dI-dC),
respectively, for 30 min at room temperature in a total reaction
mixture of 20 µl containing 20 mM HEPES, pH 7.5, 100
mM KCl, 0.2 mM EDTA, 20% glycerol, 1
mM dithiothreitol, 1 µg/µl BSA. Samples were loaded on
a 5% polyacrylamide (29:1) gel, containing 0.25 x TBE as running
buffer, and the gel was run at room temperature at 150 V for 2–2.5 h.
Excess unlabeled competitor oligonucleotide, containing the HIV B
site or a mutant B site (5'-AGCTTGTAAATTGTGGAGC-3') or antisera to
NF-B1 and RelA, was added to the reaction mixture before addition of
labeled probe. After electrophoresis, gels were dried and
autoradiographed for 1 day at -80 C.
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ACKNOWLEDGMENTS |
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Note added in Proof. Recently two papers have appeared reporting findings similar to those reported here: Heck et al. (1997) EMBO J 16:4698–4707; de Bosscher et al. (1997) Proc Natl Acad Sci USA 94:13504–13509.
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FOOTNOTES |
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This research was supported by grants from the Netherlands Asthma Foundation (92.96), the European Community (BIOMED. 2, PL 95–1358), and Boehringer Ingelheim GmbH.
Received for publication June 2, 1997. Revision received November 11, 1997. Accepted for publication December 18, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS and METHODSREFERENCES |
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B contacts DNA by
a heterodimer of the p50 and p65 subunit. EMBO J 10:1817–1825[Medline]
B and IB proteins: new
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B proteins:
multifunctional regulators of Rel/NF-B transcription factors. Genes
Dev 7:2064–2070B and the glucocorticoid receptor. Proc Natl Acad Sci USA 91:752–756B by activated glucocorticoid receptors. Mol Cell Biol 15:943–953[Abstract]
B subunit are required for negative crosstalk and direct
interaction with the glucocorticoid receptor. J Biol Chem 272:22278–22284B and C/EBPß. Mol Cell Biol 15:4971–4979[Abstract]
B and the
progesterone receptor. J Biol Chem 271:6217–6224B activity
through induction of IB synthesis. Science 270:286–290B in mediation of
immunosuppression by glucocorticoids. Science 270:283–286B
activity in endothelial cells does not involve induction of IB
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J. Zhao and K. P. Karalis Regulation of Nuclear Factor-{kappa}B by Corticotropin-Releasing Hormone in Mouse Thymocytes Mol. Endocrinol., November 1, 2002; 16(11): 2561 - 2570. [Abstract] [Full Text] [PDF]
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