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Departments of Medicine (R.E.W., J.P., K.C., S.R.) and Pediatrics (J.P., S.R.) and the J. P. Kennedy, Jr. Mental Retardation Research Center (S.R.), The University of Chicago, Chicago, Illinois 60637; Department of Human Genetics (D.F.), Mount Sinai Medical Center, New York, New York 10029; St. Jude Children’s Research Hospital (T.C.), Department of Developmental Neurobiology, Memphis, Tennessee 38105
Address all correspondence and requests for reprints to: Roy E. Weiss, M.D., Ph.D., Thyroid Study Unit, MC 3090, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637-1470. E-mail: rweiss{at}medicine.bsd.uchicago.edu
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß genes are expressed in the pituitary
gland, it is unclear what the relative roles of TR and TRß are in
TSH regulation. Experiments using over expression of artificial genes
have yielded conflicting results. The TRß knock-out mouse that lacks
both TRß1 and TRß2 isoforms provides a model to examine the role of
these receptors in TSH regulation. TRß deficient (TRß-/-) and
wild-type (TRß+/+) mice of the same strain were deprived of thyroid
hormone by feeding them a low iodine diet containing propylthiouracil
and were then treated with different doses of L-T3 and
L-T4. Thyroid hormone deprivation rapidly increased the
serum TSH level in both TRß+/+ and TRß-/- mice, reaching a
similar level in the absence of thyroid hormone. In contrast, the
decline of serum TSH by treatment with both L-T3 and
L-T4 was severely blunted in TRß-/- mice, and full
suppression was not achieved with the maximal L-T3 dose of
25 µg/day·mouse. These data indicate that TRß is not required for
the up-regulation of TSH in thyroid hormone deficiency. However,
although TR alone can mediate thyroid hormone induced TSH
suppression, TRß enhances the sensitivity of TSH down-regulation and
may be essential for the complete suppression of TSH. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TRß are
differentially expressed, the two receptors often coexist in the same
cell type (2, 3, 4). The relative contribution of the two TR genes in
mediating a particular T3 response is poorly understood
because of a paucity of in vivo functional information.
In vitro DNA-binding analyses and cell transfection
functional assays have generally indicated that three TR isoforms
(TRß1, TRß2, and TR1) bind to DNA and regulate transcription
similarly. Some studies have generated conflicting results concerning
the specific effect of TR isoforms in gene regulation. For example,
while Lezoualc’h et al. and Hollenberg et al.
(5, 6) proposed that T3-mediated suppression of TRH gene
transcription is TRß1 specific, Feng et al. (7) observed
that the same effect was mediated by each of the three TR isoforms.
Interpretation of these apparently contradictory data are complicated
because they are derived from artificial systems using overexpression
of transfected chimeric gene constructs that may not be faithful models
of events occurring in the intact animal.
The TRß knock-out mouse, which does not express either TRß1 or
TRß2 (8), provides the means to explore the relative contribution of
the TR and TRß isoforms to the regulation of physiological
responses, such as the thyroid hormone-dependent and independent
modulation of TSH. These mice display features of resistance to thyroid
hormone similar to those observed in humans with deletion of the TRß
gene (9). Both mice and humans show reduced sensitivity of thyroid
hormone-mediated suppression of TSH that manifests as persistent
secretion of TSH, despite high serum levels on T4 and
T3, ultimately leading to TSH-mediated thyroid gland
hypertrophy. Histological and immunohistochemical evidence indicates
that the defect in the TRß deficient (TRß-/-) mice that results
in chronic production of TSH is not due to any gross malformation or
hyperplasia of the pituitary but suggests instead that the defect
resides in the intrinsic function of the pituitary thyrotrophs (8).
Thus, TRß-/- mice provide a model for the detailed investigation of
the regulation of TSH expression in the absence of one specific TR
isoform through hormonal manipulations that could not be carried out in
humans.
To this purpose, we examined the effects of thyroid hormone deprivation and treatment with incremental doses of T3 and T4 on TSH in homozygous, TRß-/- mice and compared them to those observed in wild-type (TRß+/+) mice. Our data show that thyroid hormone deficiency can up-regulate TSH and that T3 and T4 can down-regulate TSH in the TRß-/- mouse. However, in contrast to the TRß+/+ mouse, the potency of thyroid hormone to down-regulate TSH is reduced, whereas hormone-independent up-regulation is intact. These results indicate that TRß does not play a role in the up-regulation of TSH in thyroid hormone deficiency and that it is not absolutely required for the thyroid hormone-mediated negative control of TSH gene expression. But, TRß enhances the sensitivity of TSH regulation by thyroid hormone and appears to be required for the complete suppression of TSH.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice were weaned on the fourth week after birth and were fed Purina Rodent Chow (0.8 ppm iodine) ad libitum and tap water. They were housed, five mice per cage, in an environment of controlled 19 C temperature and 12 h alternating darkness and artificial light cycles. All animal experiments were performed according to approved protocols at the University of Chicago.
All mice were 60–70 days old at the beginning of each experiment. Weights of TRß+/+ and TRß-/- mice overlapped and ranged from 16–21 g (female) and 17–24 g (male). Thyroid hormone deficiency was induced by feeding with low iodine (Lo I) diet supplemented with 0.15% propylthiouracil (PTU) purchased from Harlan Teklad Co. (Madison, WI).
At various intervals, approximately 300 µl of blood were obtained from the tail vein under light methoxyflurane (Pitman Moore, Mundelein, IL) anesthesia. Experiments were terminated by exsanguination through eye vein puncture under anesthesia. Serum was separated by centrifugation and stored at -20 C until analyzed in the same assay for each experiment.
In the first experiment, thyroid hormone deficiency was induced in TRß-/- and TRß+/+ mice by feeding Lo I/PTU diet for 14 days. On day 11, groups of TRß-/- and TRß+/+ mice were treated for 4 days with 0 (the vehicle only), 0.5, 5.5, and 25 µg of L-T3/mouse/daily. Twelve to 16 h after the last injection, the experiment was terminated by exsanguination. L-T3 was given by ip injections in a total volume of 0.2 ml of PBS and 0.002% human serum albumin as a vehicle. A stock solution of L-T3 (Sigma Chemical Co., St. Louis, MO) was prepared in water containing 4 mM NaOH and kept at 4 C, protected from light. The concentration of L-T3 was confirmed by RIA (Diagnostic Products, Los Angeles, CA).
The second experiment followed the same protocol of L-T3 treatment with the following modifications: no prior induction of hypothyroidism and administration of 12.5 µg rather than 25 µg of L-T3 as the highest dose.
In the third experiment, designed to determine the long-term effect of hypothyroidism and treatment with thyroid hormone, mice were fed the Lo I/PTU diet for 5 weeks and blood samples were obtained at different intervals. After the 5 weeks on this diet, mice were given 0.3 µg L-T3 daily for 3 days followed by 2.5 µg L-T3 daily for 3 additional days while continuing the same diet. Three hundred microliters of blood were obtained from the tail vein 12–16 h after the last injection of each L-T3 dose. The Lo I/PTU diet was continued and after a washout period from the L-T3 treatment, another blood sample was obtained, and treatment with 0.6 µg L-T4 daily was given for 7 days followed by 7 more days of 2.5 µg/mouse·day. Blood was obtained, as described above, at the termination of each L-T4 treatment dose. L-T4 (Sigma) at a concentration of 10 µg/ml was prepared in the vehicles as described for L-T3, above.
Serum TSH was measured in 50 µl of serum using a sensitive, heterologous disequilibrium double antibody precipitation RIA. This RIA, developed in our laboratory, uses rat TSH antiserum (TSH-S-6) provided by the National Hormone and Pituitary Program and rat-125I-TSH purchased from Amersham (Arlington Heights, IL). Mouse TSH from a serum pool of hypothyroid mice treated with the Lo I/PTU diet and serially diluted with TSH-deficient mouse serum (generated by 2-week treatment with 40 µg L-T4/mouse·day, given in the drinking water) was used as standard. The reason for using a heterologous RIA is the unavailability of purified mouse TSH suitable for labeling. Mouse TSH served as a standard because of the nonparallelism of serial dilutions of hypothyroid mouse sera as compared with rat TSH standard (TSH-RP-3) provided by the National Hormone and Pituitary Program or supplied in the Amersham rat TSH RIA kit. This held true even when rat TSH standards were diluted in the same TSH-deficient mouse serum. The concentration of TSH in the mouse TSH standard was roughly estimated from the intercept of the rat TSH and mouse TSH standard curves at 50% bound/free (B/Bo) point. The sensitivity of this assay is 0.02–0.04 ng/ml, depending on the rat-[125I]TSH batch, with intraassay coefficients of variation of 12, 13, and 4% for TSH concentrations of 0.03, 0.7, and 2.4 ng/ml, respectively. Samples containing more than 10 ng TSH/ml were 10-fold diluted with the TSH-deficient mouse serum. Serial dilutions of sera from individual TRß +/+ and TRß-/- mice rendered hypothyroid by feeding the Lo I/PTU diet, produced curves in the TSH assay that paralleled the mouse standard.
T4 was measured by a double antibody precipitation RIA (Diagnostic Products, Los Angeles, CA) modified to measure T4 in 15 µl of serum with a sensitivity of 0.5 µg/dl (6.4 nmol/liter).
Values are reported as mean ± SD P values were calculated using the Student’s t test. The value of the limit of assay sensitivity was assigned to samples with undetectable TSH and T4 concentration.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). These
differences were observed in subsequent experiments, showing from 5- to
10-fold higher TSH and from 2- to 1.6-fold higher T4 in TRß-/- as
compared with TRß+/+ mice (
Figs. 1–3).
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) was to determine the role of TRß in
both the up- and down-regulation of TSH by thyroid hormone deprivation
and excess, respectively. Fourteen days of Lo I/PTU, produced a decline
in serum T4 to the same level in both TRß+/+ and
TRß-/- mice (1.35 ± 0.21 and 1.34 ± 0.43 µg/dl) and a
similar increase in serum TSH concentrations (17.5 ± 2.0 and
10.9 ± 4.8 ng/dl; P > 0.05). Treatment with
L-T3 for 4 days resulted in almost complete suppression of
TSH (0.028 ± 0.008 ng/ml) with the lowest dose of T3
in TRß+/+ mice, whereas in the TRß-/- mice, the same
L-T3 dose brought the mean serum TSH level to the value
observed at baseline. Further decline in serum TSH in TRß-/- mice
given higher doses of L-T3 was minimal, whereas in TRß+/+
mice, TSH could not be detected (<0.02 ng/ml). As expected, the
suppression of TSH by L-T3 produced a concomitant decline
in the serum T4 levels. It is of note that the Lo I/PTU
diet did not completely abolish synthesis and secretion of
T4, which in both types of mice was under TSH control
because 5.5 and 25 µg L-T3/day suppressed further the serum
T4 concentration in TRß+/+ but not in TRß-/- mice
(Fig. 1). This result also confirms that the TSH of TRß-/- mice is
biologically active. Two additional experiments were carried out to
determine the extent of down- and up-regulation of TSH in the absence
of TRß.
In Exp 2, down-regulation of TSH by T3 was examined in
groups of TRß+/+ and TRß-/- mice without prior induction of
hypothyroidism, so that changes could be observed from baseline (Fig. 2). The lowest dose of L-T3 reduced the serum TSH below the
limit of detection by the assay (<0.04 ng/ml) in six out of eight
TRß+/+ mice. With the same L-T3 dose, the mean TSH in
TRß-/- mice was not significantly different than that in TRß-/-
mice receiving the vehicle only. Higher doses of L-T3
resulted in a dose-dependent decrease of serum TSH, though complete
suppression was not achieved in TRß-/- mice even with 12.5
µg/day. The decline of serum T4 paralleled that of TSH in
both types of mice indicating the RIA is measuring biologically active
TSH.
In Exp 3, up-regulation of TSH was examined by maintaining the thyroid
hormone deprivation for 5 weeks with Lo I/PTU diet (Fig. 3). TSH values
reached maximal levels and plateaued after 4 weeks of Lo I/PTU diet in
both animal groups. They were significantly higher (2.5-fold) in the
TRß-/- as compared with the TRß+/+ mice. This is most likely due
to the reduced sensitivity of TRß-/- mice to the suppressive effect
of the residual T4 secreted during treatment with Lo I/PTU
diet. As observed in Exp 1, L-T3 was less potent in
suppressing serum TSH in the TRß-/- mice. On the higher
L-T3 dose, the mean TSH concentration in TRß+/+ mice
(0.074 ± 0.030 ng/ml) reached the value observed at baseline
(0.084 ± 0.042 ng/ml), whereas the TSH concentration in
TRß-/- mice (2.96 ± 1.46 ng/ml) was 3.5-fold above the
baseline value (0.86 ± 0.26 ng/ml). Administration of
L-T4 for 2 weeks also failed to completely suppress TSH in
the TRß-/- mice (Fig. 3). When the plots correlating the mean
levels of serum TSH and T4 are extrapolated to zero
T4, the values of TSH are 58.7 and 58.3 ng/ml for the
TRß+/+ and TRß-/-, respectively (Fig. 4). This result supports the notion that
the differences in serum TSH in the presence of even low levels of
thyroid hormone is due to the reduced potency of the hormone in
TRß-/- mice.
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Discussion |
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1, TRß1, and
TRß2 (11). These ligand-dependent nuclear transcription factors
regulate target genes by binding to specific thyroid hormone response
elements, either as homodimers or as heterodimers in association with
retinoid x receptors. Also, evidence indicates that TRs are
capable of mediating both thyroid hormone-dependent and thyroid
hormone-independent transcriptional control, possibly involving
recently defined corepressors and coactivators (12, 13, 14, 15). There is ample experimental evidence that unliganded TRs exert a silencing effect on genes regulated positively by thyroid hormone (16, 17, 18), and it has been suggested that unliganded TRs have constitutively stimulating effect on genes regulated negatively by thyroid hormone (5, 6, 19). That the latter effect has physiological relevance and is dependent on the concentration of TR has been recently shown by the over expression of TRß in mouse liver (20).
Because both TR and TRß genes are expressed in the pituitary
gland, either one or both can be implicated in the mediation of
T3-dependent suppression and T3-independent
up-regulation of TSH gene expression in vivo. However,
because this is one of the rare locations where TRß2 messenger RNA
(mRNA) is relatively highly expressed, it has been suggested that
TRß2 may have a particular role in the regulation of TSH gene
expression (1). Transfection studies have failed to demonstrate with
certainty whether the regulation of TSHß subunit gene is TR isoform
specific (21) or whether other genes, such as the TRH gene, may respond
selectively to distinct TR isoforms (5, 6, 19). Furthermore, studies on
TSH regulation in subjects from the single family with resistance to
thyroid hormone due to TRß gene deletion (9) have been inconclusive
owing to the unavailability, at that time, of a sensitive TSH assay
(22, 23). Thus, the TRß deficient mouse provided the opportunity to
examine the role of TRß in the regulation of TSH under the conditions
of thyroid hormone deprivation and excess. More specifically,
experiments were designed to determine the role of TRß, the
quantitative effect of total unliganded TR in the up-regulation of TSH,
and the ability of thyroid hormone to down-regulate TSH in the absence
of TRß.
In comparison to humans lacking TRß who have twice the normal serum
TSH concentration (9), the TRß-/- mice have on the average 5- to
10-fold higher serum TSH concentrations than the TRß+/+ controls. In
patients expressing mutant TRß genes that cause the dominantly
inherited form of resistance to thyroid hormone, TSH has enhanced
biological activity (24). No information on the bioactivity of TSH in
subjects with TRß deletion is available, and methods do not allow
measurement of bioactivity in mice. Differences in the bioreactivity of
mouse and human TSH may explain the relatively higher level of
immunoreactive TSH in TRß-/- mice compared with patients without
TRß. Not withstanding this difference between man and mouse, the
mechanism for the reduced sensitivity to thyroid hormone in TRß-/-
mice is that of increased TSH gene transcription since the accumulation
of TSHß and subunit mRNAs are increased by 3.3- and 2.5-fold
respectively (8).
The absence of TRß did not impair the up-regulation of TSH induced by
thyroid hormone deprivation. The significantly higher peak TSH level
achieved in TRß-/- vs. the TRß+/+ mice is likely due
to the stronger inhibitory effect of the residual thyroid hormone in
TRß+/+ mice, the synthesis of which could not be completely inhibited
by the Lo I/PTU diet. This is supported by the finding that mean serum
TSH levels in TRß+/+ and TRß-/- are not different when
extrapolated to zero T4 in thyroid hormone deprived animals
treated with graded doses of L-T4 (Fig. 4). Thus the
unliganded TRß does not contribute to the up-regulation of TSH. We
have previously reported that fibroblasts from subjects lacking the
TRß gene show no compensatory increase in TR1 mRNA (25).
Similarly, it has been shown that in TRß-/- mice there is no
obvious compensatory alteration in the levels of TR1 or TR2 mRNA
in a variety of tissues (8). This was confirmed at the protein level by
the finding of 30% and 80% reduction in total nuclear
T3-binding capacity in brain and liver, respectively,
suggesting that expression of TR is unaffected by TRß (26). If TSH
up-regulation was indeed mediated through the combined effect of
unliganded TRs, the magnitude of serum TSH increase in TRß-/- mice
should have been lesser. Failure to observe a truncated up-regulation
of TSH in TRß-/- mice suggests that 1) TSH up-regulation is not
mediated by unliganded TR, or 2) unliganded TR alone and/or another,
as yet unidentified TR isoform, are sufficient for the full induction
of TSH gene expression. In model 1) above, up-regulation may be a
default mechanism not actively involving TRs but perhaps mediated by
other signaling pathways, such as TRH. These possibilities remain to be
explored.
The targeted mutation in the mouse TRß gene inactivates its function but leaves the 5'- end of the coding region intact (8). In these mice, some expression of the amino terminal fragment of TRß1, and possibly TRß2, could be demonstrated by immunohistochemical analyses of brain tissue (26). Although this truncated peptide does not bind to DNA or T3, we do not know how it may interact with cofactors.
In contrast, the potency of thyroid hormone to down-regulate TSH was
reduced, and it is not sure that complete suppression of TSH can be
achieved at all in TRß-/- mice. Increase of the L-T3
dose to 50 µg/mouse·day produced sickness and death in both
TRß+/+ and TRß-/- mice. A longer period of L-T4
administration, which is a more potent inhibitor of TSH (20), also
failed to completely suppress TSH in TRß-/- mice. In conclusion,
these results suggest that TRß is not required for the up-regulation
of TSH and although TR can mediate thyroid hormone induced
suppression of TSH, the presence of TRß enhances the sensitivity to
thyroid hormone and is required for the full suppression of TSH.
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Footnotes |
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2 Supported by a Sinsheimer Scholarship.
3 Supported by Deutsche Forschungsgemeinschaft (DFG) PO
556/1–1.
Received April 10, 1997.
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