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Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611
Address all correspondence and requests for reprints to: J. Larry Jameson, M.D., Ph.D., Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Tarry 15–709, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: ljameson{at}nwu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(ER) messenger RNA was present in FRTL-5 cells using a
RT-PCR assay and was confirmed by Western blot analysis. An
estrogen-responsive reporter gene was transfected into FRTL-5 cells to
test the functionality of the endogenous ERs. Estradiol increased the
activity of the reporter gene, and the antagonist, ICI182780, inhibited
ER-dependent transcription. To extend this analysis, we examined the
effect of estradiol on FRTL-5 cell growth. Estradiol increased FRTL-5
cell growth in a time- and concentration-dependent manner in either the
absence or presence of TSH. Because iodine is known to inhibit thyroid
cell growth, the effect of estradiol on the expression of the
sodium/iodide symporter (NIS) was assessed as a potential target of
estrogen action. Estradiol blocked TSH-induced NIS expression, and
treatment of cells with estradiol and ICI182780 restored TSH-induced
NIS expression to normal levels. These data demonstrate that FRTL-5
cells contain functional ERs that enhance cell growth and inhibit
expression of the NIS. The demonstration of a direct effect of
estradiol on thyroid follicular cells raises the possibility that it
may play a role in the sexually dimorphic prevalence of goiter. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The prevalence of goiter is much greater in women than in men regardless of geographic distribution (2, 8, 9). The decline in the prevalence of diffuse goiter with age is inversely related to the increase in the frequency of thyroid nodules and thyroid antibodies (8, 9). In areas of low iodine intake, elderly women have a higher prevalence of goiter than do men. However, when the ingestion of iodine is high, the prevalence of goiter in the elderly is similar for both sexes (10).
It is unclear why women are more susceptible to goiter than men. In part, it may reflect increased susceptibility to autoimmune thyroid disease in women, even if it is subclinical (11). Alternatively, pregnancy could increase the demands for iodine, resulting in increased thyroid growth (12, 13, 14). The increased risk of goiter might also relate to the presence of greater amounts of estrogen in the female, which could have direct or indirect effects on thyroid cell growth and/or function. A direct influence of estradiol (E2) in thyroid follicular cells has not been described despite multiple reports of estrogen receptors (ERs) in the thyroid (15, 16, 17, 18, 19, 20, 21). In this report, we examined the effect of estrogen on the growth of FRTL-5 cells, a differentiated rat follicular cell line derived from the thyroid gland of the Fischer rat under defined culture conditions that has been widely adopted as a model system for the study of thyroid cell function (22).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RNA extraction and RT-PCR
Total RNA was extracted using RNeasy (QIAGEN,
Valencia, CA) according to the manufacturer’ s specifications. RNA (2
µg) was deoxyribonuclease (DNase) treated with 2 µl buffer B [at a
1:10 dilution, the composition is 6 mM Tris-HCl (pH 7.5),
50 mM NaCl, 6 mM MgCl2, and 1
mM dithiothreitol] and 1 µl RQ1 ribonuclease-free DNase
I (1 U/µl), and the reaction was incubated at 37 C for 30 min. To
inactivate DNase activity, 1 µl DNase Stop Solution was added, and
the reaction was incubated at 65 C for 10 min. For RT, 5 µl (500 ng)
DNase-treated RNA were added to a 20-µl reaction mixture containing 4
µl 5 x avian myeloblastosis virus RT buffer, 2 µl 10
mM deoxy (d)-NTPs, 1 µl RNAsin, 1 µl 500 ng/µl random
hexamers, 1.5 µl avian myeloblastosis virus reverse
transcriptase, and 5.5 µl diethylpyrocarbonate-treated water. All
reagents were purchased from Promega Corp. (Madison, WI).
RT was carried out at 25 C for 10 min, 42 C for 30 min, and 99 C for 10
min and was terminated at 4 C.
For PCR amplification of rat ER and RPL19 (internal control)
complementary DNAs (cDNAs), the following sense and antisense primers
were used for ER: 5'-AAT TCT GAC AAT CGA CGC CAG-3' and 5'-GTG CTT
CAA CAT TCT CCC TCC TC-3'. For PCR amplification, 3 µl cDNA were
added to a 50-µl reaction containing 5 µl 10 x reaction
buffer [670 mM Tris (pH 8.8), 67 mM
MgCl2, 160 mM
(NH4)2SO4, and 100 mM
ß-mercaptoethanol], 26 µl ddH2O, 5 µl
dimethylsulfoxide, 7.5 µl 10 mM dNTPs, 1.5 µl sense and
antisense primers (25 pmol/µl), and 0.5 µl Taq DNA
polymerase (5U/µl). Reactions were carried out at 94 C for 3 min; 40
cycles of 94 C for 1 min, 56 C for 1 min, and 72 C for 1.5 min; and
then 72 C for 15 min and 4 C to terminate.
Immunoprecipitation and Western blot analysis
Nuclear extracts were prepared as described previously (24), and
ER protein was immunoprecipitated as follows. Four hundred
micrograms of nuclear extract of FRTL-5 cells, T47D cells, and TSA
cells (three different vials) were incubated with 20 µl Protein A/G
Plus-Agarose (Santa Cruz Biotechnology, Inc., Santa Cruz,
CA) for 1 h at 4 C. After centrifugation at 4000 x
g for 5 min at 4 C, the supernatant was incubated on ice for
3 h with 4 µg anti-ER antibody (ER Ab-3: AER 308,
recognizing the amino acids 120–170 of ER; Neo Markers, Fremont,
CA). Supernatants from TSA cells were also treated with 4 µg
antimitogen-activated protein kinase antibody (anti-MAPK; Santa Cruz Biotechnology, Inc.) or no antibody as a control. Each
complex was washed three times and separated by centrifugation for 2
min at 16,000 x g in buffer containing 50
mM Tris-HCl (pH 8), 150 mM
NaCl, 1% Nonidet P-40, 50 mM NaF, 0.1 mg/ml
phenylmethylsulfonylfluoride, 10 µg/ml aprotinin, 1
mM dithiothreitol, and 0.2 µM okadaic acid.
The complexes were then washed twice in buffer containing 10
mM Tris-HCl (pH 7.5) and 10 mM
MgCl2 and resuspended in 20 µl of the same buffer. The
samples were kept at -70 C. For Western blot analysis, 10 µl of each
sample were added to 7 µl sample buffer [0.5 M Tris-HCl
(pH 6.8), 10% glycerol, 10% SDS, 5% ß-mercaptoethanol, and 1%
bromophenol blue], heated for 4 min at 94 C, subjected to SDS-PAGE,
and then transferred to a polyvinylidene difluoride membrane (Hybond-P,
Amersham Pharmacia Biotech, Aylesbury, UK). The blot was
blocked in PBS/1% Tween-20 (Sigma Chemical Co.) and 5%
nonfat dry milk for 1 h at room temperature and then exposed for
1 h at room temperature to a 0.1% Tween-20/PBS solution
containing 1 µg/ml of a solution of anti-ER antibody (C-314,
Santa Cruz Biotechnology, Inc.) recognizing amino acids
280–335 of ER. After six washes of 5 min each in 0.1%
Tween-20/PBS, the blot was incubated in a 1/3300 dilution of
peroxidase-linked secondary antimouse antibody (Promega Corp.) for 1 h at room temperature. After washing the
membrane as described above, the proteins were detected by
autoradiography with the ECL-Plus chemiluminescent detection system
(Amersham Pharmacia Biotech).
Growth assays
The MTS assay for cell growth was performed according to
the manufacturer’s protocol (CellTiter 96 Aqueous NonRadioactive Cell
Proliferation Assay, Promega Corp.). This is a
colorimetric assay to determine the number of viable cells. The assay
is based on the cellular conversion of the tetrazolium salt,
(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)
inner salt), into a formazan that is soluble in tissue culture medium
and is measured directly at 490 nm in 96-well assay plates. Absorbance
is directly proportional to the number of living cells in culture.
FRTL-5 cells (4 x 103/well) were plated in 96-well
plates in 3H medium (described above). After 4 days, cells were washed
once with PBS and starved in 2H medium, with one change in the interim.
Cells were then treated for 48 h as follows, in four different
experiments: 1.1) dose effect of E2 (0, 10-11,
10-10, 10-9, 10-8, and
10-7 M) combined with 20 µIU/ml TSH (data
not shown), 1.2) dose effect of TSH (0, 10, 20, 30, 40, and 50
µIU/ml) combined with 10-8 M E2
(data not shown), 1.3) ICI effect (100 nM) on
E2 (10 nM)-induced growth, and 1.4) ICI effect
(100 nM) on E2 (10 nM)- and TSH
(0.02 mIU/ml)-induced growth. Ethanol was added as necessary so all
treatment medium had a 0.2% final ethanol content, and media were
changed after 24 h. ICI182780 was obtained from ICI
Pharmaceuticals (Macclesfield, UK), and 17ß-estradiol was obtained
from Sigma Chemical Co.
The total DNA amount, as an index of cell growth, was assessed using the diphenylamine method. Four days after plating 4 x 104 cells/well of a 24-well plate, cells were washed once with PBS, starved for 7 days (-TSH) with one change, and then treated as follows in two different experiments: 2.1) effect of E2: control group (2H medium), E2 group (2H and 10 nM E2), and E2 plus ICI group (2H, 10 nM E2, and 100 nM ICI); and 2.2) effect of E2 associated with TSH: control group (2H medium and 0.02 mIU/ml TSH), E2 group (2H medium, 0.02 mIU/ml TSH, and 10 nM E2); and E2 and ICI group (2H, 0.02 mIU/ml TSH, 10 nM E2, and 100 nM ICI). Ethanol was added as necessary so all treatment media had a 0.2% final ethanol content, and the media were changed after 24 h. After 48 h, cells were washed twice with cold PBS, and cold 5% trichloroacetic acid was added for 15 min to 4 days at 4 C. Trichloroacetic acid was aspirated, and a developing solution [20 ml A solution (500 mg diphenylamine, 45 ml glacial acetic acid, and 1 ml 18 M H2SO4), 8 ml ddH2O, and 280 µl 1% acetaldehyde] was added for 24 h. The results were read at 580 nm (Du 640B spectrophotometer, Beckman Coulter, Inc., Schaumburg, IL) and calculated according to the standards.
All experiments designed to study growth were repeated at least three times and gave essentially the same results. The data shown are those of a representative experiment.
Transfection and luciferase assay
FRTL-5 cells were seeded onto 12-well plates in 3H medium as
described above. At approximately 60–75% confluence, 500 ng of the
ERE2-tk109-luc or the tk109-luc expression vectors (25) were
transfected into appropriate wells using Lipofectamine Plus Reagent
(Life Technologies, Inc.) according to the manufacturer’s
suggested protocol. After transfection, the cells were treated with 2H
or 3H medium (described above) containing ethanol, 10-8
M E2, or 10-8 M
E2 plus 10-7 M ICI182780. Ethanol
was added to each treatment group to a final concentration of 0.2%.
Luciferase activity was determined approximately 48 h after
hormone treatment using an AutoLumat LB953 luminometer (EG & G, Salem,
MA) as previously described (25).
Semiquantitative RT-PCR of the rat sodium-iodide symporter
(NIS)
Cells were grown in 10-cm plates in 3H medium to 70%
confluence, washed with PBS and starved for 7 days in 2H medium, with
one change, and then treated for 2 days (with a change after 24 h)
as follows: control group (2H medium), E2 group (2H medium
and 10-8 M E2), TSH group (2H
medium and 1 mIU/ml TSH), TSH and E2 group (2H medium, 1
mIU/ml TSH, and 10-8 M E2), and
TSH, E2, ICI group (2H, 1 mIU/ml TSH, 10-8
M E2, and 10-7 M ICI).
Ethanol was added to each treatment group to a final concentration of
0.2%. Each group had seven plates except the E2 group
(four plates). RNA was extracted as described above, and cDNA was
produced in two different reactions for each RNA extracted.
For PCR amplification of rat NIS and rat ribosomal S16 protein (S16),
used as an internal control, the following sense and antisense primers
were used: for NIS, 5'-ATC CTC TCC TCA CCG AGT CA-3' and 5'-CGC AGC TCT
AGG TAC TGG TA-3' (expected size, 500 bp); and for S16, 5'-TCC AAG GGT
CCG CTG CAG TC-3' and 5'-CAG GGT CCG ATC GTA CTG GA-3' (expected size,
355 bp). For the PCR reaction, 6 µl cDNA were added to a 50-µl
reaction containing 5 µl 10 x reaction buffer (as described
above), 9 µl 25 mM MgCl2, 20.9 µl
double-deionized H2O, 2.5 µl dimethylsulfoxide,
2.5 µl 25 mM dNTPs, 1.5 µl sense and antisense primers
(25 pmol/µl) for NIS, 0.3 µl sense and antisense primers (25
pmol/µl) for S16, and 0.5 µl Taq DNA polymerase (5
U/µl); all reagents were obtained from Promega Corp. A
reaction mix (premix) was prepared with all the reagents and 0.7–2
µCi [-32P]dCTP/reaction (250 µCi/µl;
Amersham Pharmacia Biotech). cDNAs were added to 44 µl
premix, and reactions were carried out at 94 C for 3 min; 23 cycles of
94 C for 1 min, 55 C for 1 min, 72 C for 3 min; and then 72 C for 15
min and 4 C to terminate. The PCR products were separated on an 8%
polyacrylamide gel. The gels were dried and analyzed with a
PhosphorImager (Storm 860, Molecular Dynamics, Inc.,
Sunnyvale, CA). A ratio between the image obtained with NIS and that
obtained with S16 in the same reaction was calculated.
Statistics
The 
-square test was used for comparisons between two groups.
For comparisons involving multiple groups, nonparametric one-way ANOVA
was used. All P values were two sided; P <
0.05 was considered to indicate statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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was performed. As a positive control, total RNA was
extracted from rat prostate, a tissue in which ERs are relatively
abundant (26, 27). The ribosomal messenger RNA (mRNA), RPL19, was
amplified as an internal control. As shown in Fig. 1
, ER was identified in FRTL-5 cells
and in the rat prostate, with the expected size of 344 bp. RPL19 was
amplified with the expected size of 500 bp.
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protein. Extracts from T47D cells
(positive control) and TSA cells (negative control) were also isolated.
Proteins in the FRTL-5, T47D, and TSA cell extracts were
immunoprecipitated using a monoclonal antibody that recognizes amino
acids 120–170 of ER. The immunoprecipitated proteins were analyzed
by Western blotting using a second monoclonal antibody that recognizes
amino acids 280–335 of ER. As shown in Fig. 2, a 67-kDa band, consistent with the
expected size of ER, was seen in FRTL-5 and T47D cells, but not in
the extract from TSA cells. Immunoprecipitation of TSA cells with
H2O or an anti-MAPK antibody (negative control) also did
not identify any immunoblotted protein.
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, 10-8 M E2 stimulated the
transcriptional activity of an estrogen-responsive reporter gene,
ERE2-tk109-luc, which contains two estrogen response elements linked to
the luciferase gene. The transcriptional effect of E2 does
not require the cotransfection of ER-expressing plasmids and occurs via
endogenous receptors. As a negative control, E2 did not
increase the transcriptional activity of the control vector tk109-luc,
which contains the thymidine kinase promoter but no estrogen response
elements. TSH also induced reporter activity compared with that in a
group in the absence of TSH and E2 (data not shown), but
the addition of E2 further increased gene activation
(P < 0.016). Estrogen-dependent transcription was
blocked by the receptor antagonist ICI182780 (P <
0.005). Also, ICI182780 when added alone did not have an effect on
reporter activity (data not shown).
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, 10-8
M E2 increased the growth of FRTL-5 cells, and
this effect was fully abolished by the ER antagonist, ICI182780, in
both the absence (Fig. 4A) and presence (Fig. 4C) of 20 µIU/ml
TSH.
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, 10-8
M E2 increased the DNA content of FRTL-5 cells,
and this effect was fully abolished by ICI182780 in both the absence
(Fig. 4B) and presence (Fig. 4D) of 20 µIU/ml TSH.
Effect of E2 on expression of NIS mRNA
The effect of E2 on sodium/iodide symporter gene
expression was studied in FRTL-5 cells that were deprived of TSH as
described in Materials and Methods. Semiquantitative RT-PCR
was performed for NIS mRNA, using S16 as an internal control. Amplified
NIS and S16 cDNAs showed the expected sizes of 500 and 355 bp,
respectively. The ratio of NIS/S16 autoradiographic signal intensities
was calculated for each sample. As shown in Fig. 5, TSH stimulated the expression of NIS
mRNA. E2 blunted TSH-induced expression, and this effect
was fully abolished by ICI182780. E2 had no significant
effect on the level of NIS mRNA in the absence of TSH.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in FRTL-5 cells
and a direct effect of E2 on the growth and function of
these cells. RT-PCR demonstrated the presence of ER mRNA, and
Western blots confirmed the presence of the protein. ERs have been
identified previously in normal and abnormal human thyroid tissue by
immunohistochemistry (15, 17, 18, 28) and binding assays (19, 20). More
recently, ER mRNA was detected by RT-PCR in both human thyroid glands
and cell lines derived from a rat primary thyroid tumor (19, 21).
However, immunohistochemical detection of proteins using
peroxidase-based methods sometimes fails to detect ERs (29, 30) and
could be affected by the presence of high endogenous peroxidase
activity in thyroid follicular cells, which could lead to nonspecific
results (29). It was necessary to demonstrate the presence of functional ERs in FRTL-5 cells. E2, at a concentration of 10-8 M, was able to further increase the activity to the estrogen-responsive ERE2-tk109-luc reporter gene in addition to TSH. This effect was blocked by the addition of ICI182780. The estrogen induction of this reporter is relatively modest in FRTL-5 cells, especially compared with that in breast cancer cells, where in parallel experiments using T47D cells, we typically observed a 5- to 10-fold stimulation (data not shown). Variable responses to nuclear receptors are common in different cell lines. This interesting phenomenon presumably could reflect differences in the transcriptional coactivators and other components of the transcriptional complex. In addition, the level of responsiveness often relates to the basal activity of the reporter gene.
The effect of E2 on FRTL-5 cell growth was assessed by two different techniques, the MTS assay and DNA content. With both assays, E2 increased the rate of cell proliferation. As these effects were fully abolished by ICI182780, a competitive inhibitor of estrogen action, they support a specific effect of E2 on thyroid follicular cell growth. The observation that the E2 effect occurs in the absence or presence of TSH suggests that it acts independent of the TSH signaling pathway. The cellular mechanism by which E2 stimulates thyroid cell growth is unknown. However, it may share certain features with breast cancer cells, another target tissue in which estrogen stimulates cell growth (31).
The effects of iodine on thyroid cell growth and function are complex and are highly dependent on the apparently opposing actions of TSH and iodine (32, 33). A modification of the medium that serves to increase TSH-induced growth, such as an increase in serum concentration, is accompanied by a reduced ability of the cell to uptake iodide (34). A reduction in the thyrocyte iodine content makes the cells more sensitive to TSH action (35, 36, 37). In view of the important role of iodine in thyroid cell growth, we examined NIS expression as a potential target of E2 action. This gene encodes the sodium/iodide symporter, the protein responsible for iodide uptake in the thyroid follicular cell (38). It is known that TSH can increase iodide uptake in a dose-dependent manner (34, 39), and this effect is correlated with a rapid increase in NIS gene expression (40). It is of interest to note that although submaximal TSH concentrations were used to ensure detection of an E2 growth effect, a greater concentration of TSH (1 mIU/ml) was used in the NIS RT-PCR experiments to correspond to the dose used to maintain the FRTL-5 cells.
In this study, E2 reduced TSH-stimulated NIS gene
expression, and this effect was reversed by ICI182780. However, in the
absence of TSH, E2 did not affect NIS expression. This
finding is similar to the effects of some growth factors, such as
epidermal growth factor (EGF), transforming growth factor- (TGF),
and activin, which increase the growth of thyroid cells and reduce
their ability to uptake iodide only in the presence of TSH (41, 42, 43, 44).
E2, in different cell types, has been shown to increase
mRNA and protein expression of growth factors such as EGF, TGF, and
IGF-I (45). Coincidentally, the action of EGF-mediated stimulation of
ER transcriptional activity was abolished by a pure antiestrogen (45).
There is also evidence that the MAPK signal transduction cascade is
involved in growth factor enhancement of ER action (45). The MAPK
pathway as well as the induction of growth factors such as EGF or
TGF are well described in thyroid cells (32) and could be involved
in estrogen action in the thyroid.
The demonstration of ER in FRTL-5 cells concomitant with the ability of E2 to increase cell growth and reduce NIS gene expression may represent a pathway that is involved in goiter formation. If the reduction in NIS gene expression is accompanied by a reduction in thyroid gland iodide content, it could explain why women develop goiter more frequently than men. In addition, a partial block of iodide uptake by estrogen could increase urinary iodine excretion, thus contributing to the iodine loss that is associated with pregnancy (46, 47).
Recently, it was suggested that the human thyroid gland has the potential for estrogen synthesis, raising the possibility of an autocrine or paracrine role for estrogen (28). In our studies, ICI was able to partially inhibit FRTL-5 cell growth in the absence of added estrogen (data not shown). This is likely to reflect the presence of a low level of endogenous estrogen activity in the serum or medium. Further studies should be performed to extend our understanding of the role of E2 in thyroid cell physiology and its possible contribution to the pathogenesis of human goiters.
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Acknowledgments |
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Footnotes |
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Received May 21, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and ß-subunit promoters by AP-2. J Biol Chem 272:15405–15412
and -ß, and progesterone receptor mRNA expression in various
prostatic lobes and microdissected normal and dysplastic epithelial
tissues of the Noble rats. Endorcrinology 139:424–427
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