Department of Medicine, University of California San Diego, La Jolla, California 92093-0618
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ABSTRACT |
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We investigated the effects of the leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) on 3,3', 5-triiodo-L-thyronine, or thyroid hormone (T3)-stimulated sarcoplasmic reticulum Ca2+ ATPase (SERCA2) gene expression on cultured neonatal rat cardiac myocytes. A reduction of T3 induced increases in SERCA2 mRNA levels after co-treatment with LIF or IL-6. To investigate for the molecular mechanism(s) responsible for the blunted gene expression, a 3.2-kb SERCA2 promoter construct containing a reporter gene was transfected into cardiac myocytes. T3 treatment stimulated transcriptional activity twofold, whereas co-treatment with T3 and either of the cytokines caused an inhibition of T3-induced SERCA2 transcriptional activity. A T3-responsive 0.6-kb SERCA2 construct also showed a similar inhibition by cytokines. Cytokine inhibition of SERCA2 transcriptional activity was also evident when a 0.6-kb SERCA2 mutant, T3-unresponsive promoter construct was used. Treatment with T3 and cytokines showed a significant decrease in transcription when a reporter construct was used that was comprised of direct repeats of SERCA2 thyroid response element I. These data provide evidence for cytokine-mediated inhibitory effects on the SERCA2 promoter that may be mediated by interfering with T3 action.
cardiac hypertrophy; heart failure; contraction; relaxation; cytokines
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INTRODUCTION |
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THE EFFECTS OF THYROID HORMONE on cardiac structure and function have been extensively characterized. Thyroid hormone acts to enhance contraction velocity and increases the speed of diastolic relaxation in hyperthyroid hearts, whereas in hypothyroidism a prolonged relaxation occurs (17). Thyroid hormone action is also known to improve cardiac muscle function, including Ca2+ handling, in animal models of pressure overload cardiac hypertrophy (4). Several molecular mechanisms associated with Ca2+ transport are sensitive to the action of thyroid hormone on cardiac myocytes and include the modification, expression, and/or activity of phospholambam (18), dihydropyridine-sensitive slow Ca2+ channels (12), and the sarcolemmal Ca2+ ATPase (22).
At present, five distinct isoforms of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) are known and are encoded by three different genes. In the heart, the SERCA2a isoform is predominantly expressed (2, 3, 5, 20). We have previously demonstrated that thyroid hormone [3,3',5-triiodo-L-thyronine (T3)] induces an in vivo and in vitro pretranslational upregulation of the cardiac SERCA2 gene (20, 21). The regulation of SERCA2 gene expression by thyroid hormone is thought to occur primarily through its interaction with a group of nuclear receptors (TR), which are classified in the zinc finger family of DNA-binding proteins (6). Sequences located within 559 nucleotides upstream from the start site of transcription of the SERCA2 gene are able to confer T3 responsiveness in transient transfection assays (21). This gene has been characterized to contain three distinct thyroid hormone-responsive elements (TRE 1, 2, and 3), which regulate the transcription of SERCA2 in rat cardiac myocytes (8).
A significant downregulation of SERCA2 is known to occur in animal models of cardiac hypertrophy and failure (5). This downregulation of SERCA2 has also been documented to occur in patients who develop heart failure (1). The downregulation of SERCA2 levels correlates with impaired calcium reuptake and is thought to contribute to the development of diastolic dysfunction observed in failing myocardium (16). The downregulation of SERCA2 is also mimicked in vitro in cultured models of neonatal rat cardiac myocyte (NCM) hypertrophy (7). The molecular mechanisms responsible for SERCA2 downregulation are not well understood. It has been postulated that growth factors and mechanical overload may play a significant role. We have recently demonstrated that the hypertrophying humoral factor phenylephrine, which is capable of inducing selected gene expression in cardiac myocytes, also antagonizes the actions of T3 on SERCA2 gene expression (24).
Cytokines are pleitropic factors that are thought to modulate the communication between the immune and hematopoietic systems (23). The cytokines leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) belong to the IL-6 class of cytokines, which include oncostatin M, interleukin-11, and ciliary neurotrophic factor (23). LIF and IL-6 are known to act through the glycoprotein 130 (gp130) receptor and activate several second messenger pathways (13, 19). The addition of LIF or IL-6 to cultured cardiac myocytes induces a hypertrophic phenotype (14). Similar observations have been obtained using in vivo experimental animal models (10). Interestingly, although high levels of circulating cytokines occur in patients with cardiac hypertrophy and heart failure (15), their capacity to antagonize the action of T3 on SERCA2 gene expression has not been explored.
In this study, we assess the effects of LIF and IL-6 on thyroid hormone-induced SERCA2 gene expression in NCM. Results indicate a blunting (i.e., downregulation) of T3-upregulated SERCA2 mRNA levels, which is evident upon co-treatment with T3 and LIF or T3 and IL-6. Transient transfection experiments of NCM with SERCA2 promoter plasmids reveal that LIF and IL-6 partly inhibit T3-induced transcriptional activation of the SERCA2 promoter. Thus these results suggest a potential negative modulatory role for cytokines on cardiac SERCA2 gene expression. These actions may arise from a repressing action of LIF and Il-6 on T3-induced SERCA2 trancriptional activity.
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METHODS |
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Cell culture and treatment. Primary cultures of rat ventricular NCM were prepared as described previously (21). Briefly, ventricles from 1- to 2-day-old neonatal rats were minced, digested with collagenase and pancreatin, and subjected to discontinuous Percoll (Pharmacia LKB Biotechnology) gradient centrifugation. The myocyte-enriched fraction was washed twice, resuspended in a 4:1 ratio of DMEM to medium M-199 (GIBCO) supplemented with antibiotics (penicillin, streptomycin, and fungizone; GIBCO) plus 10% (vol/vol) horse serum and 5% (vol/vol) fetal bovine serum (FBS) stripped of thyroid hormone using Bio-Rad AG1-X8 resin (Bio-Rad, Richmond, CA) (24). Cells were plated at a density of 2 × 106 cells/10 cm tissue culture dish precoated with 1% (wt/vol) gelatin. Cell preparations were judged to be >95% myocytes as verified through morphological features. For experiments performed to evaluate changes in gene expression, NCM were placed in serum-free media (DMEM-M-199 + 0.1% BSA) overnight followed by treatment with or without LIF (10 ng/ml, BioSource International), IL-6 (10 ng/ml, BioSource International) and T3 (Sigma Chemical, St. Louis, MO). For transient transfection experiments, cells were treated in the presence of maintenance media (DMEM-M-199) + 3.4% (vol/vol) stripped horse serum + 1.6% FBS stripped of thyroid hormones. For transient transfection experiments, cells were treated in the presence of maintenance media (DMEM-M-199) + 3.4% (vol/vol) horse serum + 1.6% FBS stripped of thyroid hormones.
RNA isolation and Northern blot analysis.
Total cellular RNA was isolated using the guanidium isothiocyanate
phenol/chloroform method. The yield and purity of RNA samples was
assessed by ratio optical density at 260 and 280 nm. For hybridization, total RNA was size fractionated by denaturing agarose gel
electrophoresis. RNA was visualized by ethidium bromide staining,
transferred to nylon membrane in 10× standard saline citrate
(SSC) by capillary diffusion and fixed by ultraviolet cross-linking.
Hybridization was performed with a 1.7-kb EcoR I fragment from
clone pCC1 as a cDNA probe (21). After hybridization, the membranes
were washed with increasing stringency from 2× SSC-0.1% SDS at
room temperature to 0.1× SSC-0.1% SDS at 55°C before
exposure to Kodak XAR 5 film (Eastman Kodak, Rochester, NY). To correct
for differences in loading, membranes were dehybridized and
rehybridized with a 29-bp DNA oligonucleotide complementary to 28s
ribosomal RNA. The oligonucleotide was a 5' end labeled using
[-32]dCTP and terminal deoxynucleotide
transferase. Corrections for loading differences were made by dividing
the intensity of the hybridization signals obtained with the SERCA2
cDNA probe by the intensity of the hybridization signals obtained with
the 28s probe. Quantification of autoradiograms was performed by
scanning densitometry with the NIH Image software.
Plasmid constructs.
The rat 3.2-kb rat SERCA2 promoter chloramphenicol acetyltransferase
(CAT) expression vector used in this study contains the 3.2-kb upstream
promoter sequence of the SERCA2 gene fused to the bacterial gene coding
for CAT inserted into a promoterless vector, pBLCAT3 (21). The parent
vector contains translational termination signals and a simian virus 40 polyadenylation signal to enable the expression of CAT protein in
eukaryotic cells. The 0.6-kb SERCA2 construct is the truncated form of
the 3.2-kb promoter but still encompasses the three functional TREs.
The M123 plasmid construct is equivalent to the wild-type 0.6-kb
construct but has inactivating mutations at the three TREs that change
T to A, thus making the promoter construct unresponsive to
T3. The TRE I SERCA2 luciferase plasmid construct used
contained an oligonucleotide comprising TRE I
(5'-CAGGGCGCGGAGGCAAGCCAAGGACACCAG-3') upstream of a
minimal SERCA2 promoter (positions 38 to +32) cloned into the
luciferase vector pGL2basic. Five micrograms of rat thyroid hormone
receptor (Tr
1) (24) were used (i.e., contransfected) in
all transfection experiments.
Transient transfection assay.
NCM were transiently transfected with a total 20 µg of DNA/10-cm dish
by use of a calcium phosphate-DNA co-precipitation method (24). When
this method was used, an average transfection efficiency of
20-30% was obtained. Briefly, NCM were transfected with 7 µg of
3.2-kb SERCA2 CAT reporter plasmid DNA, 3 µg pCMV -Gal (CMV, cytomegalovirus;
-Gal,
-galactosidase), 5 µg rat Tr
1, and
the empty vector pBS to compensate for a constant total DNA. After 16-20 h of incubation at 3% CO2, the precipitate was
washed off, and the NCM were placed in maintenance medium (DMEM-M-199)
containing 5% FBS with or without LIF or IL-6. Forty-eight hours after
treatment, NCM were harvested in 0.25 M Tris · HCl,
pH 7.5, and cells were lysed through freeze-thawing. The cellular
debris was pelleted, and the supernatant was collected and aliquoted
for
-Gal and CAT assays.
-Gal activity was measured by the
o-nitrophenyl-
-D-galactopyranoside, or ONPG
method, and CAT assays were performed using thin-layer chromatography
(24). CAT activities were normalized to their corresponding
-Gal
activities to correct for the variation in transfection efficiency.
Experiments were performed independently
3 times (each in
triplicate). Luciferase activities were also normalized to their
corresponding
-Gal activities.
Data analysis.
Results of multiple experiments (9-12 data points from 3-4
individual experiments) are shown as means ± SD or SE.
Results were analyzed for statistical significance using In Stat
software. Statistical comparison was performed using ANOVA and
Dunnett's post hoc test for group comparisons at a level of
significance of P 0.05.
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RESULTS |
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LIF and IL-6 diminished T3-induced SERCA2 gene
expression in neonatal cardiac myocytes.
It has previously been shown that T3 stimulates SERCA2 gene
expression and increases SERCA2 mRNA levels in vitro and in vivo. The
effects of LIF and IL-6 stimulation on T3-dependent SERCA2 gene regulation in NCM were examined using Northern blot analysis. NCM
were serum starved for 24 h, as previously described in METHODS, and were subsequently treated with 1 nM T3, with or
without 10 ng/ml LIF or IL-6 for 48 h. Figure
1A shows a representative Northern blot autoradiogram probed with a SERCA2 cDNA probe. An oligonucleotide probe directed against 28s was used to correct for loading differences. Results from three independent experiments are summarized in Fig. 1B. SERCA2 mRNA levels in cells treated with
T3 increased to 1.78 ± 0.4 vs. control values
(1.0 ± 0.2). SERCA2 mRNA levels decreased by 20% (0.8 ± 0.17) in
NCM that were treated with IL-6 alone, whereas cells treated with LIF
saw their levels decrease to 0.9 ± 0.10. Concomitant treatment with
T3 and LIF (1.48 ± 0.2), or T3 and IL-6
(1.21 ± 0.27) resulted in a blunted T3
upregulation of SERCA2 mRNA levels (P < 0.05). Thus cytokine
stimulation of NCM in the presence of thyroid hormone inhibits the
accumulation of SERCA2 mRNA.
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LIF and IL-6 downregulation is also evident in the wild-type minimal
promoter for SERCA2.
NCM were transfected with the 0.6-kb SERCA2 wild-type construct to
determine whether the truncated form of the promoter shows a similar
pattern of downregulation to the 3.2-kb promoter plasmid. Treatment
with 1 nM thyroid hormone alone stimulated 0.6-kb SERCA2 promoter
activity to 2.5 ± 0.4-fold over control unstimulated levels (Fig.
3). LIF and IL-6 decreased basal
transcription of the minimal SERCA2 promoter by 40-60% (0.4 ± 0.14 and 0.6 ± 0.15, respectively; P < 0.01) compared with
control untreated NCM. Interestingly, NCM that were treated with
T3+LIF (0.82 ± 0.07) or T3+IL-6 (0.85 ± 0.20) significantly (P < 0.01) decreased thyroid hormone
upregulation of SERCA2 promoter activity in the setting of the
minimal-response 0.6-kb promoter. Thus, at the level of the minimal
SERCA2 promoter, the inhibitory effect of LIF and IL-6 on SERCA2
transcriptional activation is still evident.
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Effects of LIF and IL-6 on T3 upregulation of SERCA2 are
in part mediated by the TRE.
As an alternative approach to assess whether the downregulatory effect
of LIF and IL-6 on T3 upregulation of SERCA2 is mediated at
least partly through TREs, the direct repeat TRE I of the rat SERCA2
promoter was used in transient transfection assays. The reporter
plasmid pGL2b without insert was transfected as a DNA control and
exhibited no responsiveness (data not shown). Results are summarized in
Fig. 5. Cells treated with 1 nM
T3 generated a fourfold enhanced transcriptional activity.
Cells treated with LIF and IL-6 (10 ng/ml) alone did not yield modified
transcriptional activity. However, cells treated with
T3+LIF or T3+IL-6 showed a significant decrease
in transcription as assessed through luciferase activity (P < 0.05). Thus these results suggest that cytokine-induced inhibition of
SERCA2 transcriptional activity does occur at least partly by
modulating TRE I responsiveness to thyroid hormone.
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DISCUSSION |
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The heart is an important target organ for thyroid hormone action, and hypothyroidism can induce delays in diastolic relaxation (17). These changes are closely linked to intracellular calcium homeostasis, which is also severely altered in the failing human myocardium (1). Our initial findings from SERCA2-overexpressing transgenic animals (9) indicate that increased SERCA2 expression results in enhanced calcium transients, myocardial contractility, and relaxation. These findings support a contributory role for depressed levels of SERCA2 in heart failure dysfunction. Thus an understanding of the molecular mechanisms that are responsible for depressed levels of SERCA2 becomes important in elucidating potential therapeutic strategies.
Increased serum levels of cytokines have been recently demonstrated to occur in experimental animal models and human patients with heart failure (15). Cytokines are a class of humoral factors that were originally described as mediators of immune and hematopoietic responses (23). Recently, cytokines have also been shown to induce a hypertrophic cardiac phenotype. Specifically, the cytokine cardiotropin-1 induced cardiac myocyte hypertrophy both in vitro and in vivo (10, 11, 14). In a study by Hirota et al. (10), it was demonstrated that transgenic mice overexpressing IL-6 and IL-6 receptors developed cardiac hypertrophy. Thus the importance of understanding how cytokines affect thyroid hormone-induced SERCA2 gene expression and translation becomes of interest given the role of SERCA in calcium handling and transport within the myocardium.
Using an in vitro model of cultured NCM, we report the finding that the cytokines LIF and IL-6 have the capacity to downregulate thyroid hormone-induced gene expression and transcriptional activity of SERCA2. Specifically, we observed that thyroid hormone-induced SERCA2 mRNA levels are significantly decreased in the presence of LIF or IL-6. This decrease in mRNA is evident at the level of transcriptional activation, as derived from results obtained in transient transfection studies utilizing the full-length 3.2-kb SERCA2 and 0.6-kb SERCA2 constructs. The downregulatory action of cytokines on SERCA2 trancriptional activity appears to be a combination of effects on the SERCA2 promoter, in part independent of TREs but also exerting effects through TREs. These results are derived from using the 0.6-kb SERCA2 M123 mutant promoter constructs and TRE I, a direct repeat promoter construct.
Our results indicate that, in the absence of T3, LIF and IL-6 have the capacity to downregulate SERCA2 mRNA levels by 10-20% from control levels. However, the concomitant treatment with T3 and LIF or IL-6 resulted in a significantly blunted T3 upregulation of SERCA2 mRNA levels by ~20-30% from control (T3 alone) levels. SERCA2 protein levels, although not assessed in these in vitro studies, are known to correspond closely with mRNA levels (7, 21).
To further investigate for the molecular mechanisms potentially responsible for reduced SERCA2 mRNA levels, we studied various SERCA2 promoter reporter constructs. Our results using our 3.2-kb promoter construct indicate a very effective capacity of LIF and IL-6 to reduce basal levels of transcriptional activity and to counteract the T3-induced increase in SERCA2 transcriptional activity. The precise mechanism(s) for the interaction between T3 and LIF or IL-6 and the site at which it takes place are currently unknown. To obtain an initial assessment of regions in the SERCA2 promoter onto which LIF or IL-6 may signal, we used 3.2-kb and 0.6-kb fragments of the SERCA2 promoter. Interestingly, the inhibitory action observed with cytokines on transcriptional SERCA2 activity by use of the 0.6-kb construct parallels that obtained with the 3.2-kb promoter very closely. These observations would suggest that the inhibitory action of cytokines may be largely exerted by affecting response elements contained within the first 600 bp. Thus a separate set of studies was undertaken to determine the capacity of LIF and IL-6 to modulate the transcriptional activity of a SERCA2 0.6-kb promoter (M123) in which all three TREs are mutated to become nonfunctional. As expected, the addition of T3 to NCM cultures transfected with the M123 promoter yielded no changes in transcriptional activity. In the absence of T3, LIF and IL-6 induced a significant reduction in M123 transcriptional activity. The addition of T3 to the treatment failed to modify this inhibitory response. These results would suggest that part of the inhibitory response may be mediated independently of TREs present on the SERCA2 promoter. To further examine this possibility, a study was undertaken that used a direct repeat TRE I of the rat SERCA2 promoter in transient transfection assays. Treatment with T3 resulted in severalfold induction of luciferase activity. Co-treatment with LIF or IL-6 resulted in a significant reduction of ~50% of T3-induced transcriptional activity. Thus these results indicate that the repressing activity of the LIF and IL-6 over SERCA2 transcription may operate in part through one or more TREs.
LIF and IL-6 mediate their actions through cytokine receptors, including the gp130 receptor, by either the JAK/STAT or the MAPK pathway (14). With the assumption that alterations in the phosphorylation status may form the basis for LIF or IL-6 action, the following TRE-associated proteins can be envisioned. Potential targets are the T3 receptor itself, retinoid X receptor forming a heterodimer with TR or co-activators linking the T3 receptor complex to the basal transcriptional machinery. The identification of the precise target of these interactions will be the subject of future studies.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-25022 and a Minority Supplement on the same award on behalf of S. Villegas.
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FOOTNOTES |
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1 Bernd Gloss and Sonia Villegas made equal contributions to this study.
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: W. H. Dillmann, Department of Medicine, Univ. of California, San Diego 0618, 9500 Gilman Dr., La Jolla, CA 92103-0618 (E-mail: wdillman{at}ucsd.edu).
Received 18 May 1999; accepted in final form 10 November 1999.
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