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Original Studies |
Institute of Anatomy (C.S., D.S., G.A.) and Department of Surgery (M.S.), University of Leipzig; and Center of Environmental Research (I.L.), Halle-Leipzig GmbH, Leipzig, Germany
Address correspondence and requests for reprints to: Dr. Gabriela Aust, Institute of Anatomy, University of Leipzig, Liebigstr. 13, Leipzig 04103, Germany. E-mail: ausg{at}medizin.uni-leipzig.de
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Abstract |
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RANTES messenger RNA (mRNA) was quantified in the thyroid tissue of 16 patients with GD and 7 patients with thyroid autonomy (TA), using competitive RT-PCR. We found a clear correlation between the RANTES mRNA level and 1) the degree of T-cell infiltration (r = 0.68), and 2) the level of serum antibodies to thyroid peroxidase (r = 0.76) in GD but not in TA patients. There was no difference between the autonomous nodules and the quiescent surrounding tissue in TA patients.
To define the cellular source of RANTES mRNA and protein, we examined
various thyroid-derived cells. Lymphocytes showed a markedly higher
basal RANTES mRNA and protein level (mean ± SEM;
pg/mL, n = 3; 140 ± 30) than thyrocytes (12 ± 5) and
fibroblasts (9 ± 2). Lymphocyte stimulation with PMA
enhanced RANTES secretion significantly (4490 ± 200). Fibroblasts
responded to stimulation with interleukin 1 (530 ± 220) and tumor
necrosis factor 
(2780 ± 1790), whereas thyrocytes did not.
However, some thyroid carcinoma cell lines showed very high basal and
stimulated RANTES expression.
Lymphocytes expressed the mRNA of all chemokine receptors that bind RANTES. The number of CCR3+ and CCR5+ T cells was significantly higher in thyroid-derived leukocytes than in those in the peripheral blood stream.
We conclude that RANTES expression, mainly by lymphocytes, is perhaps involved in the maintenance of lymphocytic infiltration and, therefore, in the autoimmune responses in GD.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The aim of our study was to investigate the expression of RANTES mRNA in the thyroid tissue of patients with GD who had low or high serum levels of antibodies against TPO and the TSH receptor [TSH-binding inhibiting immunoglobulin (TBII)]. Thyroid tissue of patients with thyroid autonomy (TA) , carefully separated in autonomous and quiescent tissue, was included in our study. The RANTES mRNA levels were related to the levels of thyroid autoantibodies and/or thyroidal T-cell infiltration. Because RANTES may be produced by a variety of cell types and induced by a variety of stimuli (12, 13), we further examined the expression and regulation of RANTES mRNA and protein in a number of thyroid-derived cells such as lymphocytes, thyrocytes, and fibroblasts. Thyroid carcinoma cell lines were used to confirm RANTES expression by thyrocytes. Expression of the CC-chemokine receptors CCR1, CCR3, CCR4, and CCR5 binding RANTES (5) was also investigated.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GD (2 males and 14 females; mean age ± SEM, 40.8 ± 2.8 yr) and TA (n = 7, all female; mean age ± SEM, 57.4 ± 2.8 yr) were diagnosed on the basis of its clinical, biochemical, and immunological features, as well as from scintiscans. Fourteen of 16 GD patients treated with methimazole or propylthiouracil for more than 8 months were clinically euthyroid and had normal free T4 and T3 levels at the time of operation. Two of the patients were undergoing surgery within 2 months after diagnosis without antithyroid drug treatment. From all patients with unifocal TA thyroid scans using Tc-99m, pertechnatate showed a single hot nodule with a low uptake in the rest of the thyroid.
Antibodies against the TSH receptor (TBII) and TPO were measured in serum obtained during the 2 weeks before operation with commercial RIA kits (Henning, Berlin, Germany). GD patients could be divided further into two groups of eight patients each: patients with high (>4000 U/mL) and patients with low (<200 U/mL) or zero serum anti-TPO levels. The correlation between the RANTES mRNA levels and the serum anti-TPO, TBII levels, or T lymphocytic infiltration (see below) was calculated by Spearman’s method.
Estimation of T-cell infiltration in thyroid sections
Thyroid samples from patients with GD were obtained at operation. The fat and connective tissue were removed immediately. In TA, the tissue was carefully separated in adenomous and quiescent tissue. In all cases, the presence of a capsule was checked. The samples were frozen and stored in liquid nitrogen until required. Cryostat sections (4 µm) were fixed in acetone (7 min), blocked, and stained with an anti-CD3 monoclonal antibody by the alkaline phosphatase antialkaline phosphatase method (all antibodies from Dianova, Hamburg, Germany), as described by Heuer et al. (14). After counterstaining with hematoxylin, the number of T cells was graded semiquantitatively (14, 15): 0 = no; 1 = few (<5%); 2 = moderate number of (5–25%); and 3 = many (>25%) positive cells. T-cell infiltration strongly correlates with the overall lymphocytic and leukocytic infiltration (14).
Preparation of thyroid-derived cells and cell lines
Thyroid-derived cells were prepared from five thyroids of patients with GD. Thyrocytes and lymphocytes were enriched after gradual enzymatic tissue digestion and cultured over a period of 16 h, as described (3). Thyrocytes were obtained from the adherent fraction by incubating the cell monolayer with PBS in the absence of Ca2+/Mg2+ for 45 min (16). Residual fibroblasts within the thyrocyte fraction were eliminated by incubating with the fibroblast-specific monoclonal antibody FibAS01 and goat-antimouse IgG-Dynabeads M450 (DynAl GmbH, Hamburg, Germany) (16). Thyroid-derived lymphocytes were enriched from the nonadherent fraction by Ficoll density gradient centrifugation (17). By culturing small pieces of thyroid tissue in DMEM (Life Technologies, Grand Island, NY) with 10% FCS, outgrowing fibroblasts were obtained, harvested, and used in the fifth to seventh passage. The purity of the isolated thyroid-derived cells was determined by using the indirect immunofluorescence technique on a FACS-Scan (Becton Dickinson and Co., Mountain View, CA) (3, 16). The human anaplastic thyroid carcinoma lines C 643, SW 1736, and HTh 74 were kindly provided by Dr. N.-E. Heldin (University of Uppsala, Uppsala, Sweden). The original dedifferentiated papillary carcinoma line 8505 C and the follicular carcinoma line FTC-133 were purchased from the German Collection of Microorganisms and Animal Cell Cultures. All cell lines were cultured in DMEM/10% FCS.
In vitro cultures
Cells (1 x 105)/well were cultured
on 24-well plates for 24 h. The medium was aspirated and replaced
with 500 µL OPTI-MEM (Life Technologies) without FCS to
eliminate possible stimulation by the latter. The medium contained the
desired concentration of human interleukin (IL)-1 (10 U/mL;
Sigma, Deisenhofen, Germany), tumor necrosis factor
(TNF-) (5 ng/mL; Sigma), lipopolysaccharide
Escherichia coli 055:B5 (LPS; 100 ng/mL;
Sigma), or 10 ng/mL PMA (Sigma). For each
stimulator, triplicate cultures were analyzed. The maximum or plateau
of RANTES mRNA or protein expression was determined with HTh 74 cells
taken as a standard. The RANTES mRNA level reached a plateau after
about 12 h and was then analyzed. The highest RANTES protein
levels were measured after 48 h. After this, the protein level
decreased, probably because of proteolytic degradation (data not
shown). In lymphocytes, the RANTES mRNA and protein levels were
examined after 6 and 12 h, because without stimulation the cells
died during this time and it was, therefore, impossible to measure the
basal quantity any later. The supernatants were removed, frozen, and
assayed for RANTES by enzyme-linked immunosorbent assay (ELISA;
Amersham Pharmacia Biotech, Freiburg, Germany). Lysis
buffer (0.2 mL) from the QIAGEN total RNA isolation kit
(QIAGEN GmbH, Hilden, Germany) was added to each well; the
contents of three wells were then pooled for each cell type and frozen
in liquid nitrogen for further mRNA analysis. The protein levels of
cultures obtained from separate experiments were presented as mean
± SEM. The Mann-Whitney test was used to
determine the statistically significant difference between basal and
stimulated cells.
RNA isolation and complementary DNA (cDNA) synthesis
Total cellular RNA was isolated from thyroid tissue and cell cultures with the QIAGEN total RNA isolation kit (QIAGEN), in accordance with the manufacturer’s instructions. Genomic DNA was digested with 0.02 U DNase/µg RNA (Roche Molecular Biochemicals, Mannheim, Germany) at 25 C for 10 min. Five micrograms of total RNA was taken to synthesize cDNA, using a first-strand cDNA synthesis kit from Amersham Pharmacia Biotech (Freiburg, Germany) in a reaction volume of 15 µL.
Semiquantitative competitive RT-PCR
Gylceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA was quantified in accordance with the published method (18). To quantify human RANTES cDNA, a rapid one-step method was introduced to synthesize an internal homologous competitor (19, 20). Amplification of thyroid tissue cDNA with the RANTES sense and RANTES hybrid primers (see Table 2) resulted in a 375-bp RANTES competitor. The competitor was purified from excess primers and dNTPs, using the QIAquick Gel Extraction Kit (QIAGEN GmbH) and quantified. The competitors were stabilized at defined concentrations in the PCR tubes by the method of Köhler et al. (21).
Variations between different cDNA preparations were corrected. All the samples were first adjusted to contain equal concentrations of GAPDH cDNA in a semiquantitative RT-PCR (20). We then estimated RANTES cDNA in these adjusted samples. cDNA samples were titrated into RT-PCR amplification solutions containing known copies of the competitor. Both the sample cDNA and the competitor were coamplified, using the RANTES sense and RANTES antisense primers. Two products were generated. One was derived from the cDNA (477 bp) and the other, 102 bp smaller in size, from the RANTES competitor. The corresponding fragments for GAPDH PCR were 567 bp (sample cDNA) and 477 bp (competitor) in length. Based on the difference in length, the sample cDNA and competitor PCR products were resolved by gel electrophoresis. The sample cDNA and competitor were quantified by measuring the intensity of ethidium fluorescence with a cooled CCD 8-bit image sensor and the data analyzed by Phoretix 1 D plus software (Phoretix International, Newcastle-upon-Tyne, UK). The target copies equation was used to determine the ratio of sample cDNA copies/PCR to the number of competitor copies added, multiplied by the quotient of the cDNA signal and divided by the competitor signal. Each 25 µL amplification reaction contained 2.5 µL 10x concentrated PCR buffer (15 mM MgCl2), 0.3 U Taq DNA polymerase (Roche Molecular Biochemicals, Mannheim, Germany), 100 µM dNTPs, 0.1 µM of each primer, 1 µL sample cDNA, and the stabilized competitor in adjusted dilutions.
Intracellular RANTES staining
The method for intracellular staining was adapted from that of Sander et al. (22). Peripheral blood (2 x 106) or thyroid-derived lymphocytes from the same patient (n = 4) were incubated with 0.1 µg/mL lipopolysaccharide and 2 µmol/L monensin (Sigma) for 24 h. The cells were washed twice in PBS/1%FCS, then fixed with 0.5 mL ice-cold 4% parformaldehyde/PBS for 10 min. After washing, the cells were resuspended in PBS containing 0.3% saponin (Sigma). The cells were incubated for simultaneous surface and intracellular staining with CD8-FITC (PharMingen Deutschland GmbH, Hamburg, Germany), CD3-CyChrome, and RANTES-PE (R&D Systems GmbH, Wiesbaden, Germany) for 30 min at 4 C. After washing, the cells were analyzed by flow cytometry.
Chemokine receptor analysis
CCR1, CCR3, CCR4, and CCR5 mRNA expression was analyzed for all
thyroid-derived cell types and thyroid carcinoma cell lines by RT-PCR
(primers see Table 1
). mRNA from
peripheral blood mononuclear cells that had been isolated by Ficoll
density gradient centrifugation served as a positive control. To
determine chemokine receptor protein expression, 2 x
105 cells were stained with directly
fluorochrome-labeled monoclonal antibodies at the desired
concentration for 20 min at 4 C (CCR5-phycoerythrin, CD3-CyChrome,
PharMingen; CCR3- phycoerythrin, R&D Systems) or by
means of an indirect immunofluorescence technique (CCR1, R&D Systems
GmbH; CCR4, Santa Cruz Biotechnology, Inc., Santa Cruz,
CA). The cells were analyzed by flow cytometry.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All the thyroid tissues investigated were RANTES mRNA positive
(Fig. 1). In GD patients, the RANTES mRNA
level correlated with the TPO antibodies (r = 0.76;
P < 0.001) and T-cell infiltration (r = 0.68;
P < 0.005). GD patients with high TPO antibodies
showed a significantly higher RANTES mRNA level
(10-21 mol RANTES
cDNA/PCR; mean ± SEM, 349 ± 72) than
patients with no or low anti-TPO antibodies (73 ± 17;
P < 0.005). Among GD patients with high TPO
antibodies, the two patients with the lowest RANTES mRNA levels showed
the least amount of TPO antibodies and of T-cell infiltration. The
RANTES mRNA level did not correlate with the TBII antibodies (r =
0.36). The RANTES mRNA levels of the two untreated GD patients, one
with zero and one with high anti-TPO levels were 67.5 and 404 x
10 -21 mol RANTES
cDNA/PCR, respectively.
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RANTES mRNA and protein expression in thyroid-derived cells
To define the cellular source of RANTES mRNA, we investigated
isolated thyroid-derived cell populations. Lymphocytes expressed a more
than 300 higher basal RANTES mRNA level than fibroblasts, and secreted
RANTES (mean ± SEM; n = 3; 140 ± 30 pg/ml)
under basal conditions (Fig. 2). PMA
(4490 ± 200 pg/mL) and LPS (480 ± 140 pg/mL)
increased RANTES secretion significantly, whereas IL-1 or TNF- did
not. This result was confirmed by flow cytometry (data not shown).
Unstimulated fibroblasts expressed RANTES mRNA near the detection limit
and secreted only small amounts of protein (Fig. 3). Stimulation with both IL-1 and
TNF- induced RANTES secretion up to 5 ng/mL after 48 h.
Thyrocytes produced small amounts of RANTES under basal conditions
(Fig. 4), and showed a slight,
insignificant increase after stimulation with IL-1 or TNF- (n =
5; basal, 12 ± 4 pg/ml; IL-1, 18 ± 7 pg/mL; TNF-,
22 ± 10 pg/mL).
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), but this increase may have been
related to the cytotoxic effects of PMA on thyrocytes, because the
number of dead cells among the thyrocytes increased conspicuously
during PMA treatment (data not shown). RANTES mRNA and protein expression in thyroid tumor cell lines
To confirm that thyrocytes may actually express RANTES, we examined five thyroid carcinoma cell lines. All of them expressed RANTES mRNA and protein under basal conditions, although the levels varied considerably. Cell lines with high levels of basal RANTES mRNA showed higher basal RANTES protein expression than cell lines with low basal levels. Unstimulated FTC-133, 8505 C, and C643 cells secreted more than 500 pg/mL RANTES. The basal RANTES mRNA (1.2 x 10-19 RANTES cDNA/PCR) and protein expression (1400 ± 24 pg/mL) by C 643 cells may be of physiological relevance.
Although FTC-133, 8505C, and SW 1736 cells express IL-1 and TNF-
receptors (20) and respond to cytokine or PMA stimulation
with an increase in granulocyte macrophage colony-stimulating factor or
matrix-metalloproteinase mRNA and protein expression (18, 20), there is no, or only a slight, up-regulation of RANTES
after stimulation (data not shown). On the other hand, basal RANTES
negative HTh 74 cells showed a strong induction of RANTES both in the
mRNA and protein levels after PMA (1100 ± 46 pg/mL) and TNF-
(1000 ± 44 pg/mL) but not IL-1 treatment.
Intracellular staining of RANTES
Compared with peripheral blood lymphocytes, a 2- to 3-fold
quantity of thyroid-derived CD3+ lymphocytes
expressed RANTES in the same patient (n = 4; mean ±
SEM; periphery: 12.9 ± 2.3%; thyroid: 35.0 ±
8.0%; P = 0.05). In the periphery (89.1 ± 3.0%)
as well as in the thyroid (92.8 ± 1.0%), most of the
RANTES+ cells were CD3+
lymphocytes. Among the
RANTES+CD3+ lymphocytes,
nearly half of the cells expressed the CD8 antigen (periphery,
41.6 ± 8.9%; thyroid, 54.1 ± 3.6%). Figure 5 shows the typical staining pattern of
one patient with GD. Thyrocytes as well a thyroid-derived fibroblasts
did not show intracellular RANTES staining (data not shown).
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Mononuclear cells circulating in the peripheral blood and
separated by density gradient centrifugation served as a positive
control for the expression of chemokine receptors. Thyroid-derived
lymphocytes and thyrocytes expressed all the chemokine receptor mRNAs
investigated. The mRNA signals obtained from leukocytes were usually
much stronger than those from thyrocytes. The cell lines, as well as
the fibroblasts, were either negative or showed only very faint signals
for CCR1, CCR5, and CCR4 mRNA. All cell types and cell lines were
positive for CCR3 mRNA (Fig. 5).
These results correlate well with the data obtained by flow cytometry.
A small number of CCR3+ cells (between 2% and
11%) were detected within each cell type analyzed. The CCR3 expression
did not correlate with the degree of activation of the cells. The few
CCR3+ and CCR5+ cells among
the thyrocytes could not be characterized as remaining leukocytes (data
not shown). RANTES chemokine receptor expression was further examined
by double labeling with an anti-CD3 monoclonal antibody on lymphocytes
in the peripheral blood and those derived from the thyroid of the same
patient (n = 3, Fig. 7). The number
of CCR3+ and CCR5+ T cells
in the thyroid was significantly higher (CCR3+
within CD3+: 15 ± 7%;
CCR5+ within CD3+: 44
± 11%) than the number of mononuclear cells in the peripheral blood
(CCR3+ within CD3+: 3
± 1%; CCR5+ within CD3+:
19 ± 5%; P < 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or
TNF- producing lymphocytes (16, 25) in the thyroid than
in the peripheral blood of the same patient during the course of GD,
even after long treatment, reflects long-standing active immunological
processes in the thyroid. Activated T cells are very potential for producing RANTES (12, 13). In our study, thyroid-derived lymphocytes showed the highest basal expression of RANTES mRNA. Intracellular staining of RANTES clearly demonstrates that thyroid-derived lymphocytes possessed a higher capacity to produce RANTES compared with peripheral blood lymphocytes of the same patient. It is not clear whether the high RANTES level is the reason for dense lymphocytic infiltration or whether the high RANTES level is caused by present lymphocytes that have received other specific chemokine signals inducing their migration into the thyroid. An autocrine feedback between recruited lymphocytes and RANTES production is also conceivable.
As the data have shown, RANTES expression is not limited to activated T cells (26). It is interesting that thyrocytes produce small amounts of RANTES under basal conditions, which suggests that one possible role of thyrocytes is to participate in the migration of T lymphocytes and monocytes into the thyroid from the blood stream. Although it is well known that in vitro thyrocytes produce a greater variety of cytokines than any other endocrine cells (27), only two chemokines, IL-8 and monocyte chemoattractant protein-1, have been investigated (28, 29). Both have been found in untreated thyrocytes as has been shown here in the case of RANTES. Intracellular staining of RANTES could not been demonstrated, probably due to the limited sensitivity of the method compared with the ELISA system.
To confirm our observations on the expression of RANTES in thyrocytes,
we examined five thyroid carcinoma cell lines. Four expressed higher
basal RANTES levels than thyrocytes. The basal or inducible RANTES
expression of all investigated tumor cell lines indicate that
thyrocytes can acquire this capability after malignant transformation.
As has already been demonstrated, cell lines from the same tissue often
produce higher RANTES levels than the normal unstimulated cells
(30). Physiologically relevant levels of intrinsic RANTES
production have been shown in the tumor cell lines from two breast
carcinomas and four of eight melanomas (30, 31). It is of
particular interest that RANTES production by tumor cells seems to be a
mediator for the recruitment of tumor-infiltrating lymphocytes and
macrophages as inhibitors of tumor growth (31, 32). RANTES
may augment the host response to tumors. On the other hand, more
malignant cells expressed higher RANTES levels than did the less
malignant cells (30, 33). Transplantation experiments in
nude mice suggest that effects of RANTES may also benefit tumor
progression. This is why data on RANTES expression by thyroid cell
lines can only be assessed in thyroid tumors. Finally, fibroblasts may
be potential RANTES producers (34). In our study, IL-1 and
TNF- induced strong RANTES secretion by basal negative
thyroid-derived fibroblasts.
To determine RANTES binding to thyroid-derived cells, we identified their expression of the chemokine receptors CCR1, CCR3, CCR4, and CCR5. All of these receptors can bind more chemokines than RANTES alone (6). Although the complex interactions between the different ligands and receptors in vivo cannot be detected by our current assays, the detection of RANTES binding receptors on thyroid-derived cells provides a first insight into the possible regulatory mechanisms. Thyroid-derived lymphocytes were positive for all the chemokine receptor mRNAs analyzed. CCR3 and CCR5 are both expressed to a greater extent by thyroid-derived T cells than by T cells in the peripheral blood of the same patient. The very small number of CCR3+ and CCR5+ T cells in the peripheral blood confirms the data reported by other groups (35). Because CCR3 expression identifies T cells capable of producing IL-4 (the key feature of Th2 cells), and CCR5 expression reflects the T-cell activation state, the more pronounced expression of CCR3 and CCR5 on thyroid-derived T cells may reflect the autoimmune process within the thyroid. Furthermore, flow cytometry analysis showed that a few cells among the thyrocytes also expressed CCR3 and CCR5, which could not be observed to contain lymphocytes. Chemokine receptor mRNAs have recently been identified on intestinal epithelial cells (36). These data indicate that epithelial cells may be able to serve as targets for chemokine signaling.
In summary, we found a clear correlation between the intensity of lymphocytic infiltration and the RANTES mRNA levels in the thyroid tissue of patients with GD. Lymphocytes themselves are the main source of RANTES in the thyroid. RANTES may use CCR3 and CCR5 to bring about the autocrine or paracrine stimulation of lymphocytes. The low RANTES levels in thyrocytes may be a feature of normal thyroid physiology. On the other hand, the high level of basal RANTES expression in some of the thyroid carcinoma lines analyzed here suggests that RANTES plays a part in thyroid tumors.
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Acknowledgments |
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Footnotes |
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Received February 25, 2000.
Revised August 2, 2000.
Accepted September 7, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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plus TNF- and inhibition by
IL-4 and IL-13. J Immunol. 154:1870–1878.[Abstract]
mRNA and protein in pathological thyroid tissue and carcinoma
cell lines. Clin Exp Immunol. 105:148–154.[CrossRef][Medline]
and TNF-. J Endocrinol. 151:277–285.[Abstract]
producing thyroid-derived T cells are detected in
Graves’ disease, thyroid autonomy as well as in non-toxic multinodular
goiter. Eur J Endocrinol. 135:60–68.[Abstract]
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200 U/mL) and high (
4000
U/mL) levels of TPO antibodies in the serum and in autonomous nodules
and the quiescent surrounding tissue of patients with TA.
