1 Department of Pediatrics, Glucocorticoids have been implicated as an
important regulator of intestinal epithelial cell ontogeny. The
polymeric IgA receptor (pIgR) is expressed in the intestinal epithelial
layer and is regulated by several mediators, including glucocorticoids.
The mechanism of how corticosteroids alter the transcriptional
regulation of pIgR expression has not
been defined. In this study, we demonstrated that glucocorticoids
upregulate steady-state pIgR mRNA
levels in the proximal intestine of suckling rats and in the IEC-6
intestinal cell line. We performed functional analysis of the
5'-flanking region in the presence of glucocorticoids and its
receptor using the intestinal cell line Caco-2. We screened 4.7 kb of
the upstream region of the murine gene and identified the most potent
steroid response element to reside between nt
ontogeny; secretory component; immunoglobulin A; mucosa; intestine
THE POLYMERIC IgA receptor (pIgR) is an integral
membrane protein that is expressed by various secretory epithelial
cells. The physiological role of the receptor is to bind and transport dimeric IgA antibodies across various epithelial layers, including the
intestine. Once the receptor-immunoglobulin complex reaches the apical
membrane of the intestinal epithelial cell, a cleaved portion of the
receptor named secretory component, remains attached to the antibody
and presumably protects it from degradation by digestive enzymes (21).
Within the intestinal lumen, secretory IgA plays a critical role in
reducing the adhesion of microbes to the epithelial layer (20).
Polymeric receptor expression is regulated by a variety of stimulants
including hormones, cytokines, growth factors, and metabolic products
(16). The receptor is also expressed in a developmentally specific
manner, and in the proximal intestine of rats mRNA levels increase
shortly after the time of weaning (5, 25). Such a developmental pattern
of expression is not unique to pIgR;
in fact several other genes expressed by the epithelial cells of the
intestine are either induced or repressed at the time of weaning (14).
Thus the acquisition by the enterocyte of the adult phenotype and the
induction or repression of these developmentally regulated proteins are
temporally coordinated at the time of weaning in a uniform and
well-documented manner (13).
A central question in the field of enterocyte adaptation is which
factor(s) is responsible for coordinating the timely regulation of
these various genes at weaning? Diamond (9) proposed a model in which
both hardwired and environmental stimuli may be responsible for
initiating the adaptive changes. In general, studies show that genes
regulated in the intestine at the time of weaning are controlled by a
poorly defined internal, hardwired clock and that changes in diet
and/or environment play only a marginal role in altering its expression
pattern (14).
The most thoroughly studied intrinsic modulators of the ontogenic
process are glucocorticoid hormones (14). In rodents, the endogenous
surge of corticosteroids occurs just before weaning, implicating this
hormone as a good candidate master control hormone. Substantial
evidence suggests that exogenous corticosteroids administered during
the suckling phase alter the level of transcription of several genes
expressed in the intestine (13). Despite this in vivo evidence and the
cloning of several of these genes, the exact mechanism of how steroids
influence the transcription of these developmentally regulated genes
has not been defined (14).
We previously reported the complete genomic organization of the murine
pIgR gene, including 4.7 kb of the
5'-flanking region (24). More recently, we have identified the
upstream 5' elements that control the basal expression of the
gene's minimal promoter in transiently transfected Caco-2 cells (24,
25). Moreover, we determined that pIgR
mRNA steady-state levels increase dramatically at the time of weaning.
To evaluate the potential role of glucocorticoids in inducing
pIgR expression, we studied both
suckling animals and the intestinal cell line IEC-6. In the current
investigation, we show that pIgR
steady-state mRNA levels are enhanced in developing intestine and IEC-6
cells treated with glucocorticoids. To define the mechanism of this
regulation, we evaluated the entire cloned upstream region (4.7 kb) of
the murine pIgR gene using transient transfection assays of sequentially shorter and mutant clones. The
glucocorticoid response element was identified and further characterized using in vitro DNase I footprint and electrophoretic mobility shift assays (EMSA).
Cell culture and DNA transfections.
The human intestinal Caco-2 cell line was cultured in high glucose (4.5 g/l) DMEM (Mediatech) containing 20% fetal bovine serum (FBS; Omega
Scientific), 100 U/ml penicillin, and 100 µg/ml streptomycin. The rat
intestinal IEC-6 cell line was maintained under similar conditions but
used 10% calf serum instead. Both cell lines were obtained from
American Type Culture Collection and grown in a humidified atmosphere
containing 5% CO2 at 37°C.
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
215 and
163
relative to the start of transcription. Substitution mutation analysis
of this region identified the location of the putative steroid response element to be between nt
195 and
176. In vitro DNase I
footprint analysis using the recombinant glucocorticoid receptor DNA
binding domain confirmed a single area of protection that spans the nt identified by mutagenesis analysis. Electrophoretic mobility shift assays of the putative element confirmed the binding of both
recombinant and cell synthesized glucocorticoid receptor in a specific
manner. In summary, we report the identification and characterization of the glucocorticoid-DNA response element located in the immediate 5'-upstream region of the murine
pIgR gene.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
6 M of dexamethasone in
charcoal-stripped 20% FBS or steroid-free medium. The cells were then
incubated for 24 h before RNA extraction.
Luciferase and -galactosidase assays.
The reporter gene assays were measured on the Monolight 2010 luminometer (Analytical Luminescence Laboratory). The luciferase assay
was done by using the enhanced luciferase assay kit by Analytical Luminescence Laboratory. The
-galactosidase measurements were done
using the Galacto-Light chemiluminescent reporter assay by Tropix. Both
assays were done according to the protocol of the manufacturer.
RNA extraction and mRNA expression.
RNA samples were taken from the duodenum of Sprague-Dawley rats and
from IEC-6 cells. The animals used were prepared as described previously (26). Corticosterone acetate (Sigma) was administered subcutaneously (100 µg/g body wt) on alternate days beginning on
day 7 of life. Tissue was isolated
from the proximal duodenum either 3 or 7 days later. RNA was extracted
by using a modified protocol of Chomczynski's guanidine isothiocynate
method. Tissue was homogenized using a Polytron and guanidinium
thiocyanate RNA extraction solution (4 M guanidinium thiocyanate, 25 mM
sodium citrate, 0.5% sodium N-lauroyl
sarcosinate, 0.7% 2--mercaptoethanol, and pH to 7 with
HCl). For IEC-6 cells, the cells were resuspended by
adding the RNA extraction solution to T75 flasks.
Plasmid construction.
The 5'-flanking region of the polymeric receptor gene was derived
from the pIgR--1-1 phage
clone, as described previously (24). The full-length
pIgR clone was constructed by
subcloning a 4.7-kb Hind III fragment
of PR-
-1-1 into a similarly digested pGL3-basic vector from
Promega. All ligations were done with the Fast Link DNA ligation kit
(Epicentre Technologies), and the correct orientation was ascertained
by restriction digestion. The nested deletion clones were created using
exonuclease III and mung bean nuclease from a kit obtained from
Stratagene. The deletions were done following the recommended protocol.
The exact sizes of the nested deletion clones were confirmed by
sequencing with the dideoxy method with Sequenase 2 (US Biochemical).
Nuclear extract preparation. Nuclear extracts isolated from Caco-2 cells transfected earlier with the GR expression vector and treated for 24 h with dexamethasone was used for EMSA (25). Samples were dialyzed in a buffer consisting of 20 mM HEPES, pH 7.9, 100 mM KCl, 0.2 mM EDTA, 20% glycerol, 0.2 mM phenylmethylsulfonyl fluoride (PMSF), and 0.5 mM dithiothreitol. The protein concentration of the extract was determined using the BCA protein assay reagent kit (Pierce).
EMSA.
The putative steroid response region was analyzed by gel mobility shift
analysis using the complementary sense
(5'-GATCAAGGAGACATTCTGTCCC-AT) and antisense
(5'-CTAGATGGGACAGAATGTCTCCTT) primers (SM3/4). Double-stranded primers were produced by boiling and then labeled with
[-32P]dCTP (3,000 Ci/mmol) using Klenow fragment and desalted through a G25 Sephadex NAP
5 column (Pharmacia). The binding reaction consisted of 6 µg of
nuclear protein extract, 5 × 104 counts/min of the SM3/4
primer, and 100- or 1,000-fold of the competitive inhibitor (when
pertinent). The master mix consisted of 5.7 mM
MgCl2, 53.8 µM
2-
-mercaptoethanol, 0.38 mM PMSF, 10 mM HEPES, pH 7.9, 10%
glycerol, 0.1 mM EDTA, 0.05 M KCl, 2.5 µg BSA, and 0.2 µg of
poly(dI/dC) (Pharmacia) in a 13-µl total mixture.
DNase I footprinting.
In vitro DNase I footprint analysis was performed according to the
established methods (25). Briefly, the
pIgR-246/+44-pGL3-enhancer clone was
digested with Bgl II and then treated
with calf intestinal phosphatase. The DNA was then kinased with
[-32P]dATP (6,000 Ci/mmol) and cut with Hind III, and
electrophoresed on a 5% polyacrylamide gel, purified, and diluted to
6,000 counts/min per ml.
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RESULTS |
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Glucocorticoids enhance polymeric receptor steady-state mRNA levels
in developing rat intestine and IEC-6 cells.
Quantitative dot-blot analysis was performed on duodenal samples
isolated from suckling rats treated initially at day
7 of life with either corticosterone or saline for
either 3 or 7 days. The blots were hybridized with labeled murine
pIgR cDNA and 18S ribosomal
oligonucleotide (data not shown) that served as a standard, and the
results were quantified by densitometry. Compared with vehicle-treated
littermates, 3- or 7-day treatment with steroids resulted in a four-
and sevenfold elevation of steady-state
pIgR mRNA levels, respectively (Fig
1A).
|
5'-Flanking region (4.7 kb) of murine pIgR gene is responsive to glucocorticoids. The nt sequence of the 5'-upstream region of the pIgR gene was examined for full palindromic GR-binding sites (GGTACANNNTGTYCT) using two standard transcriptional factor databases (30). Whereas several GRE half-sites (TGTYCT) were identified, neither database detected a potentially active full GRE palindrome in the entire 4.7 kb 5'-flanking region of the murine gene. Because no candidate hormone response sites could be identified, we tested this region experimentally using transient transfection experiments.
To study the effect of steroids on the activity of the murine pIgR promoter, the 4.7-kb pIgR-luciferase construct was used in transient transfection experiments in Caco-2 cells. Figure 2A demonstrates that in the presence of the full-length promoter (
|
Steroid responsive element was identified in immediate promoter
region of murine pIgR gene.
To identify the approximate location of the glucocorticoid-mediated
transactivation of the pIgR promoter,
transient cotransfection studies were performed using a series of 12 different size 5'-flanking constructs of the
pIgR gene and an expression vector for
GR (Fig. 2B). One day later, the
cells were either treated with dexamethasone or charcoal-stripped
steroid-free medium for an additional day before processing. Because
the basal level of expression differs between various constructs, the
data are depicted as an increase in elevation of dexamethasone-treated
cells over nonsteroid-treated cells (25). From Fig.
2B, the full-length clone
(4730/+44) shows more than an 80-fold higher level of promoter
activity compared with nontreated cells. Although promoter activity of
the longer length clones were generally 40-fold elevated in the
presence of steroids, the clones from
1254/+44 to
215/+44
consistently had a 20-fold higher level of activity compared with the
empty pGL3 basic vector. More importantly, there was a dramatic
reduction in promoter activity between the intermediate size
(
1254/+44 to
215/+44) and the smaller length
(
58/+44) clones. These data were interpreted to suggest that,
while we cannot rule out the presence of a more upstream element, the
most potent steroid response region is located between nt
215
and
58 within the murine pIgR 5'-flanking region.
Substitution mutation analysis of murine pIgR's steroid response
region.
To further refine our analysis of the steroid response element of the
pIgR gene, we tested promoter
transactivation of clones that contained mutations within the
215 to
163 region. Five clones were produced that
contained a consecutive span of 10-nt mutations within this location
(SM1-SM5). The exact nt mutated in each clone are displayed in Fig.
3 and are shown in comparison to the
sequence of the comparable region in the human and rat genes. These
mutant fragments (SM1-SM5) were subcloned upstream of the enhancer
SV40, and promoter activity was measured. Two sets of transfections
with the same mutant were either treated with medium containing
dexamethasone or steroid-free 24-h posttransfection. Transient
transfection experiments are displayed in Fig.
4 and demonstrate that promoter activity of
clones SM3 and SM4 was nearly 15% of the wild-type
246/+44
clone in the presence of glucocorticoids (P < 0.001). The nt mutated in the
SM3 and SM4 clones corresponds to bases
195 to
176 of the
murine pIgR gene, which interrupts an
asymmetric GRE (5'-TGAGACATTCTGTCCC-3') and was not
detected previously using database analysis (Fig. 3). In summary, these data were interpreted to suggest that, within the immediate 4.7-kb 5'-flanking regions of the pIgR
gene, the dominant glucocorticoid response element resides
between nt
192 and
178 upstream of the murine gene's
transcriptional start site.
|
|
DNase I analysis of murine pIgR's flanking region with recombinant
GR identifies single footprint.
To confirm the results obtained from the substitution mutation studies,
in vitro footprint analysis was performed of the murine pIgR promoter using recombinant GR
protein. We examined the region of the promoter that spans from nt
232 to
40 in the analysis. DNase I analysis demonstrated
the presence of a single footprint that spans the region mutated in
clones SM3 and SM4 (nt
195 to
176) (Fig.
5). No additional footprints could be
identified in the region studied. These data provides additional
evidence that the nt that span between
192 and
178
represent an active glucocorticoid response element.
|
EMSA of GR-binding site of pIgR gene.
To further analyze the nt within the putative steroid response element
that is responsible for binding to GR, we performed standard EMSA.
Double-stranded oligonucleotides that span the SM3 and SM4 (195
to
176) region (SM3/4) were radiolabeled and used for all
experiments. The DNA sequences of each oligonucleotide used in the EMSA
are listed within MATERIALS AND METHODS, whereas the
critical nt (within the GRE consensus) are displayed in Fig. 3. The
addition of nuclear extracts isolated from Caco-2 cells resulted in two
predominant gel shift complexes (Fig.
6A,
lane 1), and one minor complex can
be seen in the overexposed autoradiogram (open arrow heads). The
DNA-protein complex could be competed by the presence of 100- or
1,000-fold excess of either unlabeled SM3/4 (GRE) or the Out primers
(Fig. 6A, lanes 2, 3, 6, 7). The Out primer contains two clusters of
mutations in the outer portion of the GRE consensus that alters residue
+3, +4 and
5 (Fig. 3). The ability of the Out primer to compete
for GR binding suggests that the remaining critical residues (+2,
2, and
3) are sufficient to bind GR as indicated in Fig.
6A. In contrast, the band shift could
not be competed with an excess of the In oligonucleotide that contains
mutations that disrupts only residue
3, indicating its critical
role in binding GR (Fig. 6A,
lanes 4 and
5). Similarly, several other
primers designated Non and In/Out were also not capable of competing
with the complex (Fig. 6A,
lanes
8-11).
|
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DISCUSSION |
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In this study, glucocorticoids were shown to upregulate steady-state
pIgR mRNA levels in both developing
small intestine and in IEC-6 cells (Fig. 1). Transient transfection of
a 4.7-kb murine pIgR 5'-upstream
region fused to the reporter luciferase identified that the element
controlling the glucocorticoid-mediated activation of promoter activity
was located within this region of the gene. To identify the location of
the hormone response element, transient transfection of fusion
constructs containing various upstream regions of
pIgR fused to luciferase was
performed. Analysis of a series of clones identified that nt between
215 and
163 contained the putative glucocorticoid
response element (Fig. 2). Scanning mutagenesis of this region
identified that the element resides between nt
192 and
178 from the transcriptional start site (Fig. 4). This 20-nt
span identified by a combination of nested deletion and scanning
mutagenesis analysis contained an asymmetric GRE that was not
previously identified by searching with transcription factor databases
(Fig. 3). The ability of the murine element to bind to GR was further
characterized using DNase I footprint and EMSA (Figs. 5 and 6).
Although we could not definitively rule out a weak response element in
the more upstream portion of the cloned fragment, these data suggest
that the most potent steroid response element in the portion of the
pIgR gene that was studied is located
in the genes in the immediate upstream region. Interestingly, a second
asymmetric GRE is located between nt
1338 and
1352 (5'-AATACTGCCTGTCCT-3'), and its deletion from the
shorter-length clones (<1,254 bp) may account for the modest 50%
reduction of promoter activity seen in the shorter-length clones (Fig.
2).
The upstream region of the murine pIgR
gene contains several half GRE sites, which generally are insufficient
by themselves to confer hormone responsiveness. In contrast, two
half-GRE (AGAACA) separated by a three-base pair spacer are each able
to bind a GR monomer and activate promoter activity (2). When the
murine sequence is compared with that of the comparable steroid
response region in rats and humans, nt differences are limited to bases at position 5 and
6 (Fig. 3) (19, 25). In general, the
critical nt in the GRE are the four major guanine/cytosine nt at
positions ±2 and ±5 (35). Although the nt at position
5
is necessary for establishing hydrogen bond interactions with the
lysine 442 residue of GR, substitution mutation analysis reveals that
guanine, adenine, or thymine bases are equally active, whereas cytosine would dramatically reduce its steroid responsiveness (44). Therefore, we would predict that the divergent nt seen at position
5 should not dramatically alter GR binding. In contrast, the thymine at position
6 in the human response element is different from the adenine
and guanidine seen in the rat and murine element, respectively. Adenine
and guanine bases at this position are equally active, whereas thymine
would severely impair the induction of the gene by steroids (38, 44).
Interestingly, a thymine nt at position
6 should still be
capable of maintaining a marginal ability to bind to the progesterone
receptor (23).
Because glucocorticoid response elements are capable of binding to the androgen receptor, the identified element may account for the androgen responsiveness of pIgR in both prostate and in epithelial cells of the lacrimal gland (11, 37). Dexamethasone responsiveness of pIgR is also tissue specific, since production is elevated in hepatocytes and salivary cells in a dose- and time-dependent manner, while decreasing in the mammary gland and cerviovaginal secretions (5, 40, 41). Contrary to our findings, corticosteroids were previously shown to decrease the total cellular concentration of the secretory component in 10-day-old rat intestine (4).
Estrogen that binds to a slightly different hormone response element
(AGGTCANNNTGACCT) has also been shown to alter the steady-state levels
of pIgR mRNA in a complex pattern
(35). More specifically, estrogen represses
pIgR expression in the mammary gland
but enhances its synthesis in the epithelial cells of the uterus (18,
31-33, 42). The upstream region of the murine
pIgR gene contains several estrogen
half-sites and a complete palindrome
(5'-AGTTCTGCCTGACCT-3') located between nt 736 and
722 (19, 25). This particular element may account for the
responsiveness of the gene to estrogen, but it has not yet been tested experimentally.
The steroid induction of pIgR
expression may have several significant physiological consequences.
Recent in vitro evidence suggests that the receptor is also capable of
carrying antibody-antigen complexes from the basolateral to the apical
membrane (17). This represents a unique mechanism used to expel
antigen-antibody complexes from the basolateral compartment. By
upregulating pIgR expression,
corticosteroids may in turn expedite receptor-antibody-antigen interactions and enhance the removal of antigen-antibody complexes. Glucocorticoids also suppress the synthesis of several cytokines, including tumor necrosis factor-, interferon-
, and interleukin-4, which have all been shown to upregulate
pIgR expression (1, 29). Therefore,
the ultimate role that steroid administration has on
pIgR synthesis in an inflamed organ
like the adult intestine may be complex and has not been established.
Recent evidence suggests that steroid receptors alter the transcription of primary genes by interacting with several coactivators, including steroid receptor coactivator (SRC-1) and CBP/p300 (cAMP response element-binding protein). Coactivators that interact with GR have been proposed to stabilize the preinitiation complex by binding to basal transcriptional factors such as TBP, TFIID, and TFIIB which induces transactivation (27). Interestingly, several of these coactivators also have intrinsic histone acetyl-transferase activities which have been shown to induce chromatin remodeling via histone acetylation, resulting in the removal of transcriptional repressing nucleosomes (25). Therefore, coactivators may enhance steroid-induced transactivation by two mechanisms: 1) histone acetylation and remodeling and 2) stabilization of the preinitiation complex (15). Steroid-induced histone remodeling is also a general mechanism that may make promoters accessible to critical transcriptional factors. Because endogenous steroid levels in the rodent rise at the time of weaning, hormone-induced remodeling of chromatin is a plausible mechanism that may alter the expression pattern of several of these genes at weaning.
Glucocorticoids have been shown to play a critical role in the development of several organs, including the lung where among other roles it is known to induce surfactant protein D synthesis (34). The role of exogenous glucocorticoids in the precocious maturation of the intestine is also very well documented (14). Glucocorticoids have been proposed as a regulator of an intrinsic clock that controls in the expression pattern of several developmentally expressed genes in the intestine. Despite recent progress in the isolation and characterization of several such genes, including lactase and sucrase-isomaltase, investigators have yet to describe the presence of a classic glucocorticoid cis-acting element or an indirect trans-element that controls their expression (3, 43).
Although this study demonstrates that
pIgR is a primary steroid response
gene that binds GR directly, other intestinal genes may be secondary
response genes that require protein synthesis (8). Sucrase-isomaltase
may represent a secondary response gene because its induction by
steroids is delayed (22). Steroids are capable of inducing the
synthesis of several transcription factors, including C/EBP-,
C/EBP-
, C/EBP-
, and I
B, which in turn may influence the
downstream expression of a group of secondary response genes (7, 12).
Although both C/EBP-
and C/EBP-
mRNA transcripts have been
detected in the intestine, only C/EBP-
has been identified
immunohistochemically in terminally differentiated cells of the villus
(28). Such a transcription factor represents a potential mediator of
steroid-induced regulation of genes expressed in the intestine. In
fact, such a secondary response is most consistent with the
transcriptional cascade model that is appealing yet not proven in
intestinal development.
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ACKNOWLEDGEMENTS |
---|
We give special thanks to S. Smale (University of California, Los Angeles, UCLA) for helpful discussions.
![]() |
FOOTNOTES |
---|
This study was supported by the National Institute of Child Health and Human Development Grant HD-34706; Crohn's Colitis Foundation of America Grant 016714; Fellowships from the Robert Wood Johnson Foundation Faculty Training Grant and the American Gastroenterology Industry Training Award 942455; and the National Science Foundation, California Alliance for Minority Participation (E. M. Gutierrez).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. G. Martín, UCLA School of Medicine, 10833 Le Conte Ave, Dept. of
Pediatrics, Div. of Gastroenterology 12-383 MDCC, Los Angeles, CA
900951752 (E-mail: mmartin{at}mednet.ucla.edu).
Received 12 May 1998; accepted in final form 1 March 1999.
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