Departments of 1 Pediatrics and 2 Nutritional Sciences, Meriter Hospital Perinatal Center, University of Wisconsin, Madison, Wisconsin 53715
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ABSTRACT |
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Lung development and surfactant biosynthesis are
affected by retinoic acid (RA) and dexamethasone (Dex). Using a mouse
lung epithelial cell line, we are exploring RA-Dex interactions through the study of RA and Dex effects on RA receptor (RAR) and surfactant protein (SP) C mRNA expression. RA increased expression of RAR- (5.5 times) and SP-C (2 times) mRNA, with maximal effects at 24 h and at
10
6 M. The RA induction was not
inhibited by cycloheximide, suggesting RA affects transcription. With
added actinomycin D, RA did not affect the disappearance rate of
RAR-
mRNA, but SP-C mRNA degradation was slowed, indicating an
effect on SP-C mRNA stability. Dex decreased RAR-
and SP-C
expression to 75 and 70% of control values, respectively, with
greatest effects at 48 h and at
10
7 M. There was no effect
of Dex on either RAR-
or SP-C mRNA disappearance with actinomycin D. However, cycloheximide prevented the effect of Dex. Despite Dex, RA
increased both RAR-
and SP-C mRNA. This work suggests that RA and
Dex affect RAR-
and SP-C genes by different mechanisms.
gene expression; type II cells; steroid hormone superfamily; lung development; vitamin A; messenger ribonucleic acid
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INTRODUCTION |
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VITAMIN A HAS LONG BEEN recognized as essential for
lung epithelial cell differentiation, growth, and health. Vitamin A
deficiency results in loss of mucus-secreting epithelium because cells
fail to differentiate normally and to develop as layers of squamous keratinizing epithelium (7). In the human premature infant, a role for
vitamin A in prevention and/or repair of lung injury is
speculated (34). The actions of vitamin A in the lung may involve its
effects on gene regulation. Retinoic acid (RA) and 9-cis-RA, which are metabolites of
retinol, bind to nuclear RA receptor (RAR) and
9-cis-RAR (RXR) proteins, which are
ligand-activated DNA-binding proteins that belong to the steroid
receptor superfamily. Three distinct types of RARs and RXRs (,
,
and
) interact in dimer and heterodimer forms with response elements
to affect target genes (22). The characteristic expression patterns of
the different receptors suggest that they have distinct roles during
development. Specifically, in the developing lung, in situ
hybridization has demonstrated variable expression of receptors in
branching fetal mouse lung at midgestation (8, 9). Inactivation of some specific RAR isoforms in compound null mutant mice results in abnormal
lung growth and early respiratory deaths (21).
The role of RA in lung development and surfactant production is being explored in various experimental models. Regulation of the phospholipid component of surfactant by RA has been examined in in vivo studies in which maternal administration of RA increases fetal lung surfactant phospholipids and choline incorporation into phosphatidylcholine (PC; see Ref. 13). In isolated fetal rat type II cells, which produce surfactant, RA stimulates choline incorporation into PC despite its ability to inhibit type II cell proliferation (12). Type II cells isolated from vitamin A-deficient adult rats incorporate less choline into PC and disaturated PC (DSPC) compared with controls, whereas adding RA stimulates choline incorporation into both PC and DSPC in control and deficient cells (35), similar to the finding in fetal type II cells.
Fetal lung explants and lung adenocarcinoma cells have been utilized to
determine the effect of RA on surfactant protein (SP). In
13.5-day fetal rat lung cultured for up to 9 days, RA
added to the media augments the pattern of lung development toward more growth of proximal airways and also suppresses the expression of the SP
genes SP-A, SP-B, and SP-C, which usually occur in the peripheral
portions of lung during alveolar development (5). In 17- or 19-day
fetal rat lung explants, exposure to RA results in increases in SP-A,
SP-B, and SP-C mRNA, although each shows different dose-response
characteristics (4). At
1010 M RA, SP-A mRNA
maximally increases, but at
10
5 M RA, it decreases. In
contrast, 10
5 M RA
maximally stimulates SP-C and SP-B mRNA. Human fetal lung explants
treated with RA for 6 days show dose-dependent decreases in SP-A
protein and mRNA levels, a decrease in SP-C mRNA, and an increase in
SP-B mRNA (26). When H441 human lung adenocarcinoma cells are treated
with RA, SP-A mRNA levels are unaffected, but SP-B mRNA levels increase
in a dose-dependent manner (15). Together, these results are suggestive
that RA generally decreases SP-A mRNA expression, increases SP-B mRNA
expression, and has a more variable effect on SP-C mRNA in the systems
studied thus far. Cell source and the concentration and length of
exposure time to RA likely account for the variable responses noted.
Lung development is also influenced by glucocorticoids, which regulate
SP expression and affect morphological differentiation (18). In vivo
administration of glucocorticoids to pregnant rats results in
stimulation of SP genes, with SP-C mRNA increasing with the lowest dose
(11). Studies in fetal lung explants show that SP-A mRNA levels
increase at low concentrations of dexamethasone (Dex;
1010 to
10
9 M; see Ref. 3), which
is due to a stimulation of transcription. However, at higher
concentrations (10
8 M), Dex
has an inhibitory effect resulting from reduced SP-A stability.
Induction of SP-B mRNA appears to result from both an increase in gene
transcription and mRNA stability (23, 31). Dex also induces an increase
in SP-C mRNA in fetal lung explants, although reports on changes
in gene transcription and mRNA stability are mixed (2, 31).
Although the roles of Dex and RA in the lung have mostly been examined
independently, a limited amount of research has suggested that the
actions of Dex and vitamin A are interrelated. The lungs of infants
with bronchopulmonary dysplasia (BPD) display alterations in function
and morphology similar to those resulting from vitamin A deficiency
(28); postnatal Dex is a frequent treatment for these infants. Serum
retinol increased in fetuses and infants with BPD in response to
glucocorticoids (16, 36). In rats, Dex induced an increase in plasma
vitamin A simultaneously with a decrease in liver and lung vitamin A
storage (17). Specifically in the lung, the expression of RAR- mRNA
(20) and RAR binding (24) is decreased by Dex.
Although such interactions between Dex, vitamin A, and lung development exist, the mechanisms involved are presently unknown. The objective of the present study was to begin exploring this relationship by examining the effects of RA and Dex on RAR and SP-C gene expression. To determine any relationship between RA and Dex, this study evaluates their effects together in the same system, utilizing a distal respiratory cell line that can maintain a differentiated phenotype in culture. The effects of retinoids have not previously been investigated in this cell line.
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METHODS |
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Cell culture. Murine lung epithelial cell line MLE-12 (a gift of J. A. Whitsett, Children's Hospital Medical Center, Cincinnati, OH) is a clonal line representing distal bronchiolar and alveolar epithelium. It is derived from pulmonary tumors in mice transgenic for the chimeric gene composed of the simian virus 40 (SV40) large tumor antigen under transcriptional control of the promoter region of the human SP-C gene (33). The MLE-12 cell line possesses many functional and morphological characteristics of pulmonary type II cells, including typical epithelial cell morphology, presence of microvilli and multivesicular bodies, synthesis and secretion of phospholipids, and production of SP-B and SP-C. Cells were maintained in an humidified atmosphere at 37°C and 5% CO2 in modified hydrocortisone-insulin-transferrin-estrogen-selenium medium (6) containing 10 mg/ml transferrin, 4 mM L-glutamine, and 10 mM N-2-hydroxyethylpiperazine-N '-2-ethanesulfonic acid supplemented with 2% fetal bovine serum, 100 U/ml penicillin G, and 100 mg/ml streptomycin. Cells were used at passages 23-27 in culture.
Treatments.
Cells were treated with Dex (water soluble) and/or all
trans-RA that were dissolved in
dimethyl sulfoxide (DMSO). Controls with similar levels of DMSO as RA
treatment groups showed no difference in mRNA levels. RA solutions were
used under subdued lights, and culture flasks were kept dark during
treatment. For most experiments, two or three replicate flasks were
used for each experimental condition, and, to further increase sample
size, experiments were repeated various times. For determining optimum
concentration levels, cells were treated with
108 to
10
6 M RA or
10
10 to
10
6 M Dex for 48 h. From
these experiments, it was determined that 10
6 M RA and
10
7 M Dex produced maximal
effects, and therefore these concentrations were used in subsequent
experiments. To determine the effects of RA and Dex together, RA and
Dex were added simultaneously to culture media followed by incubation
for 48 h. For time-course studies, RA or Dex was added to the media,
and cells were cultured for varying lengths of time from 2 to 48 h. The
effect of the protein synthesis inhibitor cycloheximide
(CHX) was determined by incubation of cells with 0.1 mg/ml
CHX for 1 h followed by treatment with or without RA or Dex for 24 h.
Preliminary work showed no effect of 0.1 or 0.5 mg/ml CHX at 6 h.
Measurement of RNA degradation was evaluated by the use of actinomycin
D (Act D). Cells were treated with RA or Dex for 24 h, after which 0.4 mg/ml Act D was added to the media. Cells were then incubated for
various lengths of time from 2 to 12 h. The amount of mRNA present
after time was expressed relative to its 0-h control. Half-lives were
calculated from the equation:
t1/2 = ln
2/k [t1/2 is
half-life, and k is the degradation
rate constant that equals
2.303 (slope)].
Isolation of RNA and Northern and data analyses.
After MLE cells were treated as above, total RNA was extracted using
Trizol Reagent (GIBCO BRL, Grand Island, NY) as specified by the
manufacturer. Preparation of gels, transfer to nylon membranes, labeling of probes, and hybridization procedures have been previously described (20). The cDNA probes for RAR-, -
, and -
, RXR-
, and SP-C were the generous gifts of P. Chambon, Strasbourg, France, D. J. Mangesdorf, Dallas, TX, and J. A. Whitsett, Cincinnati, OH,
respectively. To correct for RNA levels, filters were also probed with
28S rRNA (Clontech, Palo Alto, CA). Filters were quantitated using a
phosphorimager (Bio-Rad, Hercules, CA). All data were normalized to
corresponding 28S rRNA levels. Treatment values were expressed relative
to mean control values.
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RESULTS |
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The MLE-12 cells contain mRNA of all three types of RARs (,
,
), RXR-
, and SP-C (Fig. 1). All
transcripts are of sizes and patterns previously reported (19, 37).
RAR-
, RAR-
, and RXR-
mRNA were not changed by RA in these
experiments (data not shown) and, therefore, were not studied further.
RA increases RAR-
and SP-C mRNA levels, with the greatest effect
occurring at 10
6 M RA (Fig.
2). RA affected the expression of both
RAR-
and SP-C mRNA in a time-dependent manner (Fig.
3). RAR-
mRNA was higher by 2 h, and
SP-C mRNA was higher by 24 h. RA at
10
6 M had the maximal
effect by 24 h on both RAR-
and SP-C mRNA, with no further
stimulation noted up to 48 h of incubation.
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Dex decreased RAR- and SP-C mRNA in MLE cells over a range of
concentrations (Fig. 4). This effect did
not occur until after 12 h of Dex treatment (Fig.
5). Dex had no effect on RAR-
, RAR-
, or RXR-
mRNA (datanot shown). In cells treated with RA, Dex did not
significantly affect the increase in RAR-
or SP-C caused by RA (Fig.
6).
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To determine the need for protein synthesis in the response of RAR-
and SP-C mRNA levels to RA and Dex treatment, the protein synthesis
inhibitor CHX was utilized. Treatment with CHX alone resulted in an
increase in abundance of RAR-
mRNA (Fig.
7), which has been shown previously (29,
32). CHX did not affect the stimulation by RA of RAR-
mRNA, but it
prevented the inhibition by Dex.
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In contrast to its effect on RAR-, CHX alone caused a marked
decrease in the level of SP-C transcripts (Fig. 7). A similar effect
has been reported on SP-A mRNA (3). The same level of decrease occurred
using a greater concentration of CHX (0.5 mg/ml; data not shown).
Addition of RA and Dex resulted in an increase in SP-C transcript
abundance above the level found in the presence of CHX alone.
To determine whether changes in RAR- and SP-C mRNA levels with RA
and Dex may be due to alterations in mRNA stability, cells were treated
with the RNA synthesis inhibitor Act D. Act D reduced the level of
RAR-
mRNA to 50% after 2.5 h and of SP-C mRNA after 12.3 h (Fig.
8). These half-lives are similar to
previously reported values (2, 30). The decline in RAR-
and SP-C
mRNA induced by Act D was similar in control and Dex-treated cells.
However, RA slightly slowed the decline 1.5-fold
(t1/2 = 18.9 h)
in SP-C mRNA; RA did not affect the RAR-
half-life.
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All of the above experiments were conducted in media containing 2%
fetal bovine serum as well as other supplements. Analysis of the amount
of retinol in one batch of serum determined that medium concentrations
of retinol were 109 M; when
this level of RA was added to media, no effect was detected on RAR-
or SP-C mRNA. Because other factors present in the media, such as
albumin and hormones, could affect results, several experiments were
conducted that compared the effects of RA and Dex on RAR-
and SP-C
mRNA in control media and in media without added serum and
hydrocortisone. There were no differences in RAR-
or SP-C mRNA
levels and the magnitude of response to RA or Dex between control and
serum-free groups.
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DISCUSSION |
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Lung differentiation, growth, and health are affected by vitamin A, as is apparent from several lines of evidence. In vivo and organ culture studies demonstrate that vitamin A deficiency causes bronchiolar and upper airway changes characterized by loss of ciliated and mucus-secreting cells and replacement of normal columnar epithelium by stratified squamous keratinizing epithelium (7). The need for retinol in cell differentiation and proliferation has been confirmed using cultures of various pulmonary cells (7). Recent genetic evidence demonstrates abnormal lung growth and early respiratory deaths in compound null RAR mice (21). Clinical findings also associate vitamin A deficiency with pulmonary morbidity (10), and some speculate that vitamin A might have a role in the prevention and/or repair of lung injury in human premature newborns (7, 36). These observations have led to recent active investigations regarding the effect of RA on lung development and surfactant in several systems.
With the increasing use of Dex both antenatally and in neonates with
BPD, a clear understanding of the mechanism of the interaction between
Dex and vitamin A is necessary because Dex has dramatic effects on
vitamin A. Dex transiently raises neonatal plasma vitamin A and
decreases liver stores (16, 35). Dex decreases RAR binding (24) and
decreases specifically the RAR- mRNA expression in rat whole lung
and fetal lung explants (20). Fetal lung development may be affected by
Dex through its ability to change fetal retinoid levels and
distribution (14), with subsequent morphological and biochemical
alterations.
The objective of the present study was to more clearly understand the
roles of RA and Dex in the lung by comparing the effects of RA and Dex
on RAR- and SP-C mRNAs. To do this, we have used the MLE cell line
in which morphological and functional characteristics of distal
respiratory epithelial cells are maintained (33). MLE-12 cells are
derived from pulmonary adenocarcinomas of transgenic mice produced by
expression of SV40 large T antigen under transcriptional control of the
bronchoalveolar-specific SP-C promoter. No prior studies have been done
to determine the effects of RA and Dex in this cell line.
Other lung carcinoma cells express all or a partial component of the
,
, and
types of RAR (27). RAR-
is usually, but not
universally, responsive to RA in these cell lines. All three types of
RARs were expressed in the MLE-12 cell line studied here, but only
RAR-
was responsive to RA, which occurred within 2 h of exposure to
10
6 M RA. The rapid
response of RAR-
mRNA to RA can be explained by the presence of a
response element for RAR-
(RARE) within the promoter of the RAR-
gene (22). SP-C mRNA also increased with
10
6 M RA, the effect
beginning after 8 h of exposure and peaking after 24 h of incubation.
Previous studies involving the effect of RA on SP-C mRNA have been
conducted in fetal lung explants (4, 15, 26) and have shown variable
results, apparently due to RA concentration and length of exposure.
The decrease in RAR- mRNA in response to Dex concurs with our
previous observations in whole neonatal rat lung, in which Dex
decreased RAR binding (24) and RAR-
mRNA accumulation (20). Studies
in vivo and in fetal lung explants demonstrate a stimulation of SP-C
mRNA in response to Dex (11, 23, 31). The inhibition by Dex of SP-C
mRNA in the MLE-12 cell line has been previously observed (J. Whitsett,
personal communication). Perhaps this indicates an absence in this
particular cell line of a type II cell-specific factor required in the
Dex response pathway.
The rapid response of RAR- to RA suggests that the regulation by RA
of RAR-
is a primary effect through the RARE. However, the slower
response of SP-C to RA and of both RAR-
and SP-C to Dex could be
indicative of a requirement for synthesis of an intermediate protein
involved in regulation of the mRNA. The results of experiments utilizing the protein synthesis inhibitor CHX suggest that the stimulation by RA of not only RAR-
but also SP-C mRNA is independent of protein synthesis. These experiments also indicate that the inhibition by Dex of RAR-
and SP-C mRNA requires protein synthesis. The effect of CHX alone on RAR-
and SP-C, however, indicates that
caution should be exercised in interpreting the data. RAR-
transcript levels are increased in the presence of CHX alone. This may
be due to inhibition of synthesis of a repressive
trans-acting factor or may result from
a nonspecific stabilizing effect on polysomal RNA (25). Simultaneously,
SP-C mRNA levels are reduced by CHX, which could result from inhibition
of an essential labile transcription factor or may involve modification
of posttranscriptional events.
Modulation of mRNA stability is an important posttranscriptional
mechanism for control of gene expression (1). In this study, mRNA
stability was assessed by the use of Act D. No change in the rate of
RAR- mRNA decline resulted from RA or Dex, but RA did somewhat
decrease the degradation rate of SP-C mRNA. Although the increase in
SP-C mRNA levels in cells treated with RA in the presence of CHX
suggests that the response to RA does not involve synthesis of a
stabilizing protein, RA may be involved in stimulating the modification
of a protein factor that stabilizes SP-C mRNA.
The different responses of the two genes studied here to RA and Dex
suggest that the effect of RA and Dex on each specific mRNA may involve
separate promoter regions in the gene with separate factors involved in
transcription. However, the lack of inhibition by Dex on both RAR-
and SP-C mRNA abundance in the presence of RA indicates some level of
interaction in the gene regulation mechanisms that is not understood at
this point. An examination of the promoter regions of these genes would
be helpful in clarifying the mechanism of action of RA and Dex. Also
important for future consideration is the role of heterodimer formation
that occurs between different steroid receptors.
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ACKNOWLEDGEMENTS |
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This work was supported by National Heart, Lung, and Blood Institute Grant 1-P50-HL-46478 and National Institute of Child Health and Human Development Grant ROI-HD-33916.
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FOOTNOTES |
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Address for reprint requests: R. D. Zachman, Univ. of Wisconsin, Meriter Perinatal Center, 202 S. Park St., Madison, WI 53715.
Received 19 May 1997; accepted in final form 23 September 1997.
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