Section of Pulmonary and Critical Care Medicine, Departments of 1 Internal Medicine and 2 Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520-8057
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ABSTRACT |
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Studies were
undertaken to define the effects of corticosteroids on stromal cell
interleukin (IL)-11 production. Unstimulated A549 epithelial-like cells
produced modest amounts of IL-11, and transforming growth factor
(TGF)-1 was a potent, dose-dependent stimulator of A549 cell IL-11
elaboration. Dexamethasone inhibited the levels of basal and
TGF-
1-stimulated IL-11 elaboration in a dose-dependent fashion. In
the setting of TGF-
1 stimulation, dexamethasone caused a >90%
decrease in IL-11 production at
10
6 M, a 50% decrease in
IL-11 production at ~1 × 10
9 M, and significant
inhibition at 10
10 M. This
dexamethasone-induced inhibition was reversed by the glucocorticoid-receptor antagonist RU-486. Dexamethasone also inhibited
respiratory syncytial virus, rhinovirus, and TGF-
1-stimulated IL-11
production by MRC-5 lung fibroblasts. In all cases, dexamethasone caused comparable changes in IL-11 mRNA accumulation. Nuclear run-on
studies demonstrated that dexamethasone caused a modest (
40%)
decrease in TGF-
1-stimulated IL-11 gene transcription. Actinomycin D
pulse-chase experiments demonstrated that dexamethasone simultaneously
destabilized IL-11 mRNA. Dexamethasone also inhibited TGF-
1-stimulated IL-11 promoter-driven luciferase activity but did
not diminish activator protein-1 binding to IL-11 promoter sequences.
Glucocorticoids inhibit lung cell IL-11 production via a complex
mechanism that involves the inhibition of IL-11 gene transcription and
the destabilization of IL-11 mRNA.
transforming growth factor-; corticosteroid; RU-486; fibroblast; messenger ribonucleic acid degradation; respiratory syncytial virus; rhinovirus
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INTRODUCTION |
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INTERLEUKIN (IL)-11 was originally cloned from primate
bone marrow stromal cells based on its ability to stimulate the
proliferation of a murine plasmacytoma cell line (27). It has since
been classified with other members of the IL-6-type cytokine family
based on the overlapping biological activities of these cytokines and
their common usage of the gp130 molecule in their multimeric receptor complexes (7, 18). Studies of the effector functions of IL-11 have
demonstrated that it is a multifunctional molecule. It is a major
regulator of hematopoiesis, with prominent effects on platelets and a
variety of other circulating cells (7). It also regulates B cell
function via a T cell-dependent mechanism (44), induces hepatocyte
production of acute phase proteins (3, 7), stimulates the production of
tissue inhibitor of metalloproteinase-1 (24), regulates neuronal
differentiation (26), influences osteoclast development (17), and has
protective effects in a variety of models of mucosal injury of the
gastrointestinal tract (20). Studies from our laboratory have
investigated the effects of IL-11 in the lung. They have demonstrated
that the transgenic overexpression of IL-11 in the murine airway
induces peribronchial inflammation; airway remodeling with fibrosis and myofibroblast and myocyte hyperplasia; and altered alveolar development (31, 39). They have also demonstrated that IL-11 has protective effects
in the lung in the setting of thoracic radiation and that the
protective effects of IL-11 may be mediated by its ability to inhibit
macrophage production of tumor necrosis factor (TNF) and other
cytokines (32, 42). Our studies of potential cellular sources of IL-11
demonstrated that human lung epithelial cells (9, 12), fibroblasts (14,
45), and smooth muscle cells (11) have the ability to produce large
amounts of IL-11 in vitro when appropriately stimulated. Potent stimuli
include transforming growth factor (TGF)-1, respiratory tropic
viruses, including respiratory syncytial virus (RSV), rhinovirus (RV),
and parainfluenza virus type III, and, to a lesser extent, IL-1,
histamine, and eosinophil-derived major basic protein (9, 12, 14, 33, 45). In contrast to our knowledge of the processes that stimulate IL-11
production, much less is known about the processes that inhibit IL-11
elaboration by stimulated stromal cells.
Corticosteroids are commonly employed in the treatment of inflammatory and fibrotic pulmonary disorders. In this and other settings, they mediate their anti-inflammatory effects, in great extent, via their ability to inhibit the production of a large variety of inflammatory cytokines. This inhibition is mediated via a variety of mechanisms, including the inhibition of gene transcription and destabilization of cytokine mRNA (5). Recent studies have demonstrated that corticosteroids can also inhibit inflammation by stimulating the production of anti-inflammatory cytokines such as the IL-1-receptor antagonist (23). The effects of corticosteroids on IL-11 production, however, have not been investigated.
To further understand the processes that regulate IL-11 elaboration,
studies were undertaken to define the effects of dexamethasone on lung
stromal cell IL-11 elaboration. These studies demonstrate that
glucocorticoids are potent dose-dependent inhibitors of TGF-1 and
virus-stimulated IL-11 elaboration by alveolar epithelial-like cells
and lung fibroblasts. They also demonstrate that these inhibitory effects are mediated by a complex mechanism that involves dexamethasone binding to the glucocorticoid receptor, the inhibition of IL-11 gene
transcription, and the enhanced degradation of IL-11 mRNA.
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EXPERIMENTAL PROCEDURES |
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Reagents
Human recombinant TGF-Cell Culture and Supernatant Collection
A549 human alveolar epithelial type II-like cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA) and were grown to confluence in 5% CO2-95% air in 100-mm petri dishes in DMEM supplemented with nonessential amino acids, L-glutamine, penicillin, streptomycin (GIBCO BRL, Grand Island, NY), and 10% fetal bovine serum (FBS; Hyclone Laboratories, Logan, UT). Once confluent, the cells were rinsed two times with serum-free DMEM and incubated in the presence and absence of TGF-IL-11 ELISA
Human IL-11 protein was quantitated by ELISA as previously described by our laboratory (11, 12, 14).mRNA Isolation and Analysis
Total cellular RNA was extracted from cell monolayers at designated time points using acid guanidinium isothiocyanate-phenol-chloroform extraction as previously described (11-14). Equal amounts (20 µg) of RNA were loaded on 1% agarose gels containing 17% formaldehyde, electrophoresed at 80 volts for 3 h, transferred to nylon membranes, and hybridized with cDNA probe labeled to a high specific activity with [Analysis of mRNA Half-Life
IL-11 mRNA stability was assessed as previously described by this laboratory (10, 47). A549 cells were incubated with TGF-Analysis of Relative Rates of Nuclear Transcription
The relative rates of nuclear transcription were assessed using modifications of protocols previously employed by this laboratory (10, 14, 47). Confluent A549 cell monolayers were incubated in the presence of TGF-Assessment of Cell Viability
Cell viability was assessed using trypan blue dye exclusion, cell counting, and measurements of cell supernatant lactate dehydrogenase (LDH). LDH was quantitated with a commercial kit (Sigma) according to the manufacturer's instructions.IL-11 Promoter-Reporter Gene Construction
As previously described (40), a 786-bp Pvu II fragment of the IL-11 promoter containing sequences betweenCell Transfection and Reporter Gene Assay
Plasmid DNA was introduced in A549 cells using a modification of the DEAE-dextran transfection protocol described by our laboratory (40, 46). Briefly, A549 cells were grown until 60-80% confluent in 60-mm petri dishes in complete DMEM with 10% FBS. They were washed and incubated with the mixture of DNA (4.5 µg) and DEAE-dextran (1 mg/ml) in a volume of 300 ml for 30 min at room temperature. At the end of this incubation period, the cells were washed and incubated in the presence and absence of TGF-Electrophoretic Mobility Shift Assay
Nuclear extract preparation. Nuclear extracts were prepared using modifications of the techniques of Schreiber et al. (36) as previously described (46). A549 cells were incubated in the presence of TGF-Oligonucleotide probes. Classic
activator protein-1 (AP-1), classic nuclear factor-B (NF-
B) and
IL-11 5' AP-1 oligonucleotides were used in these studies. The
AP-1 and NF-
B oligonucleotides were obtained commercially from Santa
Cruz Biotechnology (Santa Cruz, CA) and Bio-Synthesis (Denten, TX),
respectively. The IL-11 promoter AP-1 oligonucleotides were prepared at
the Yale University Oligonucleotide Synthesis Facility. Their sequences
were as follows: classic AP-1,
5'-CGCTTGATGACTCAGCCGGAA-3'; classic NF-
B,
5'-TGGACAGAGGGGACTTTCCGAGAGGC-3'; and IL-11 5' AP-1,
5'-GGGAGGGTGAGTCAGGATGTG-3'.
Electrophoresis. Electrophoretic
mobility shift assays (EMSA) were performed using modifications of the
techniques of Schreiber et al. (36) as previously described (40, 46).
Radiolabeled double-stranded oligonucleotide probes were prepared by
annealing complementary oligonucleotides and end labeling with
[-32P]ATP and T4
polynucleotide kinase (New England Biolabs, Beverly, MA). The labeled
probes were purified by push-column chromatography, diluted with buffer
(1 mM Tris · HCl, pH 8.0, and 1 mM EDTA) to the
desired concentration, and incubated with equal aliquots of nuclear
extract and poly[dI-dC] at room temperature
for 30 min. Resolution was accomplished by electrophoresing 10 µl of
the reaction solution on vertical 6% nondenaturing polyacrylamide gels
containing 2% glycerol using 22.3 mM Tris · HCl,
22.3 mM boric acid, and 0.25 mM EDTA, pH 8.0. DNA-protein binding
activity was assessed via autoradiography.
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RESULTS |
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Dexamethasone Regulation of TGF-1-Stimulated IL-11
Production
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Dexamethasone Regulation of TGF-1-Stimulated IL-11
mRNA Accumulation
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Role of Cytotoxicity and Glucocorticoid Receptor
Studies were undertaken to determine whether cell cytotoxicity played a role in mediating the inhibitory effects of dexamethasone and whether these inhibitory effects were mediated via an interaction of dexamethasone with the glucocorticoid receptor. Cell cytotoxicity was assessed via trypan blue dye exclusion and LDH release. In all experiments, dexamethasone-mediated cell cytotoxicity was not appreciated. A comparable level of trypan blue dye exclusion and LDH release was seen in cultures of A549 cells incubated in the presence and absence of TGF-
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Specificity of Dexamethasone Effect
Previous studies from our laboratory demonstrated that, in addition to epithelial cells, lung fibroblasts are potent producers of IL-11 (14). In addition, we demonstrated that a variety of respiratory tropic viruses can stimulate stromal cell IL-11 elaboration (9, 12). Thus studies were undertaken to determine whether the inhibitory effects of dexamethasone were specific for TGF-
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Unstimulated MRC-5 fetal lung fibroblasts produced detectable levels of
IL-11 in the absence of exogenous stimulation. The levels of IL-11
produced by these cells were increased further by TGF-1 and RSV
(Fig. 7). Dexamethasone inhibited the basal levels of IL-11 production by unstimulated MRC-5 cells (data not shown). Dexamethasone was also a potent dose-dependent inhibitor of
TGF-
1- and RSV-stimulated IL-11 mRNA accumulation and protein production by MRC-5 cells (Figs. 6 and 7). This inhibition was comparable in potency to the inhibition noted in A549 cells. Thus the
IL-11 inhibitory effects of dexamethasone are not specific for TGF-
1
or A549 alveolar epithelial-like cells.
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Dexamethasone Regulation of IL-11 Gene Transcription
Nuclear run-on assays were used next to characterize the effects of glucocorticoids on IL-11 gene transcription. IL-11 gene transcription was barely detectable or undetectable in nuclei from unstimulated A549 cells (data not shown). In contrast, IL-11 gene transcription was readily appreciated in nuclei from TGF-
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Dexamethasone Regulation of IL-11 mRNA Stability
To further define the mechanism(s) of dexamethasone inhibition, we compared the rates of degradation of IL-11 mRNA transcripts in cells stimulated with TGF-
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Dexamethasone Regulation of IL-11 Promoter Activity
Previous studies from our laboratory demonstrated that TGF-
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Dexamethasone Regulation of AP-1 in A549 Cells
Our previous studies demonstrated that TGF-
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DISCUSSION |
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Glucocorticoids are extremely important therapeutic agents that are
extensively utilized to treat inflammatory and fibrotic pulmonary and
nonpulmonary disorders. In accord with this widespread clinical use,
the mechanisms of glucocorticoid action have been analyzed extensively.
Studies in the 1950s and 1970s suggested that steroids mediated their
effects via their ability to stabilize lysosomal membranes and inhibit
arachidonic acid metabolism, respectively (reviewed in Ref. 5). Later
studies focused on the ability of steroids to inhibit the production of
proinflammatory cytokines and suggested that this inhibition is the
major anti-inflammatory mechanism of steroid action (5). Most recently,
it has become clear that the effects of steroids are cytokine specific.
Although a wide variety of inflammatory cytokines are inhibited by
glucocorticoids, a variety of others are either not inhibited or
augmented in a modest fashion (5, 23). To further define the biological profile of corticosteroids, we characterized the effects of
glucocorticoids on human lung stromal cell IL-11 production. Our
studies demonstrate that glucocorticoids inhibit TGF-1- and
virus-stimulated IL-11 production by lung fibroblasts and epithelial
cells. Importantly, they also demonstrate that the doses of
dexamethasone that mediate these effects are in the range of the
concentrations used clinically and approximate the concentrations that
are present under physiological circumstances.
Studies of the cellular and molecular mechanisms of glucocorticoid
action have demonstrated that glucocorticoids can mediate their effects
via their ability to alter the transcription of target genes
and/or their ability to alter the posttranscriptional processing and degradation of target gene mRNA (5, 47). Our studies
demonstrate that dexamethasone inhibits IL-11 protein production and
that this inhibition is associated with a comparable decrease in IL-11
mRNA accumulation. This indicates that this inhibition is mediated, to
a great extent, via a pretranslational mechanism. Nuclear run-on assays
demonstrated that this decrease in IL-11 mRNA accumulation was due, in
part, to glucocorticoid inhibition of IL-11 gene transcription.
However, the magnitude of transcriptional inhibition could not fully
explain the observed decrease in steady-state mRNA. This apparent
discrepancy was explained, at least in part, by our finding that
glucocorticoids also destabilize IL-11 mRNA. Thus steroids inhibit
IL-11 production via a complex mechanism(s) that involves the combined
action of transcriptional and posttranscriptional inhibitory processes.
These findings are in accord with previous studies from our laboratory
demonstrating that transcriptional and posttranscriptional regulatory
events mediate the inhibitory effects of glucocorticoids on fibroblast IL-6 production (47) and studies from other laboratories showing similar patterns of corticosteroid regulation of interferon-, IL-2,
and granulocyte-macrophage colony-stimulating factor (5, 28, 41).
Glucocorticoids are believed to inhibit gene transcription via a
variety of mechanisms. At least four mechanisms have been proposed.
They include 1) the direct
interaction of the ligand-bound glucocorticoid receptor
with a cis-acting "negative
glucocorticoid response element" in the regulatory region of the
gene. This mechanism, although unusual, may mediate the effects of
glucocorticoids on prolactin and pro-opiomelanocortin (6, 34);
2) the binding of the ligand-bound
glucocorticoid receptor to positive-acting cis elements in the basal promoter and
enhancer sequences, thereby blocking stimulatory
trans-acting factors.
This may be the mechanism by which glucocorticoids inhibit osteocalcin
transcription and IL-6 promoter reporter gene activation in HeLa
epithelial cell lines (29, 38); 3)
the binding to and direct inactivation of transcription factors such as
AP-1 and NF-B (19, 30); and 4)
the induction of inhibitory proteins such as the inhibitor of NF-
B,
which sequesters NF-
B transcription factors in an inactive form in
cellular cytoplasm (2, 35). Previous studies from our laboratory
demonstrated that TGF-
1 stimulation of stromal cell IL-11 production
is mediated, to a great extent, at the level of gene transcription (14,
40). More recent studies have demonstrated that this stimulation is
AP-1 dependent and is associated with enhanced AP-1-DNA binding
activity in these cells (40). To further understand the mechanism by
which glucocorticoids regulate TGF-
1-stimulated IL-11 gene
transcription, studies were undertaken to determine if glucocorticoids
could regulate the expression of an IL-11 promoter-reporter gene
construct and alter TGF-
1-stimulated AP-1-DNA binding. These studies
demonstrated that a promoter construct that contains the important AP-1
sites in the IL-11 promoter was inhibited in a potent dose-dependent
fashion by dexamethasone. In accord with our previous findings,
TGF-
1 was an effective inducer of AP-1-DNA binding in A549 cell
nuclei. Glucocorticoids did not, however, inhibit this induction. These
observations suggest that glucocorticoid inhibition of
TGF-
1-stimulated IL-11 gene transcription is not mediated via the
ability of the ligand-bound glucocorticoid receptor to
quantitatively alter AP-1-DNA binding. All in all, they raise the
possibility that these inhibitory effects are mediated via an
AP-1-independent mechanism. The recent demonstration of a functional NF-
B site in the IL-11 promoter (4) supports this contention and
raises the possibility that glucocorticoid regulation of NF-
B activity may play a role in this response. Our conclusions regarding AP-1 must be viewed with caution, however. It is well known that very
complex alterations in AP-1 transcription factor subunit composition
can be seen in the setting of TGF-
1 stimulation (40). Thus the
present studies do not rule out the possibility that corticosteroids
inhibit IL-11 transcription by altering AP-1 subunit composition.
Further studies will be required to determine with certainty whether
AP-1 is involved in the inhibition of IL-11 induced by dexamethasone.
Gene expression can be regulated, both positively and negatively, by alterations in the stability of mRNA transcripts. Previous studies from our laboratory demonstrated that IL-1 and TNF interact to selectively stabilize IL-6 mRNA transcripts (10). Conversely, IL-4 has been shown to destabilize cytokine mRNAs (16). In the present study, we show that glucocorticoids inhibit IL-11 production, in part, by destabilizing its mRNA. This finding is in accord with previous studies by Yang and Yang (43) demonstrating that heparin also inhibits IL-11 protein production and gene expression via a similar posttranscriptional mechanism. The mechanism by which the mRNA transcripts are destabilized is poorly understood. It has been proposed, however, that cytokine mRNA degradation and destabilization are mediated, in part, by AUUUA motifs (37), which have recently been redefined as UUAUUUAUU motifs (21, 48). These AU-rich sequences are present in the 3'- untranslated region of IL-11. Proteins that interact with these sequences in labile mRNAs, such as the AUUA-binding factors (8, 25) or factors that bind to other sequences in the 3'-untranslated region (1), are felt to mediate this destabilization. Additional investigation will be required to define the cis elements in the 3'-untranslated region of IL-11 that mediate the effects of corticosteroids and the trans-activating factors that bind to these locations.
Our studies of the biological effects of steroids were prompted by a desire to understand the ramifications of steroids when they are administered in the setting of tissue inflammation and ongoing repair. The anti-inflammatory effects that result from steroid inhibition of cytokines such as IL-1, IL-2, and TNF can be understood easily. The consequences of steroid inhibition of IL-11 production are, however, more complex. Studies from our laboratory and others have demonstrated that IL-11 can activate B and T cells (44) and can cause mononuclear cells to accumulate around small bronchioles in the murine lung (39). In contrast, IL-11 also appears to have immunosuppressant and protective effects. These can be easily appreciated in studies from our laboratory and others that demonstrated that IL-11 can inhibit macrophage production of IL-1, TNF, and IL-12 (22, 32, 42) and exert protective effects in the setting of thoracic irradiation (32) and colonic mucosal injury (20). Thus the effect that steroid inhibition of IL-11 would have at the tissue level would depend on whether the pro- or anti-inflammatory effects of the cytokine predominated at that time and at that location. Should steroids inhibit the production of IL-11 that is playing a protective role, adverse consequences of this inhibition might be noted.
In summary, these studies demonstrate that dexamethasone is a potent
dose-dependent inhibitor of TGF-1-stimulated IL-11 production by a
variety of stromal cells. They also demonstrate that this inhibition is
mediated via a complex mechanism that involves the inhibition of gene
transcription and destabilization of IL-11 mRNA. Last, these studies
demonstrate that dexamethasone inhibition of IL-11 gene transcription
is not associated with a decrease in TGF-
1-induced AP-1-DNA binding,
raising the possibility that this inhibition is mediated via an
AP-1-independent mechanism.
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ACKNOWLEDGEMENTS |
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We thank the investigators and institutions that provided the reagents that were employed and Kathleen Bertier for excellent secretarial and administrative assistance.
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FOOTNOTES |
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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: J. A. Elias, Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St., 105 LCI, New Haven, CT 06520-8057.
Received 5 June 1998; accepted in final form 14 October 1998.
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