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Original Studies |
The First Department of Internal Medicine (T.A., I.M., A.K., O.I., K.Z., Y.T., S.E.), University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu, Japan; and Ito Hospital (N.I., Ku.I., Ko.I.), Tokyo, 150-8308, Japan
Address correspondence and requests for reprints to: Isao Morimoto, The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, 1–1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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, and proliferation of thyrocytes by the cellular
adhesion via the ICAM-1/LFA-1 pathway was independent of the
proliferative response of these cytokines. Taken together, these
results suggest that lymphocytes infiltrating GD thyroid induce
proliferation of GD-thyrocyte by the cellular adhesion to thyrocytes
via ICAM-1/LFA-1, which may lead to the development of a goiter. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Intercellular adhesion molecule-1 (ICAM-1), a member of the Ig G gene
superfamily, is characterized as a major natural ligand to lymphocytic
function-associated antigen-1 (LFA-1), a member of the integrin ß2
subfamily, which is seen on lymphocytes (5). ICAM-1 is expressed on a
variety of cells, fibroblasts, vascular endothelial cells, and thymic
epithelial cells and has been recognized on human thyrocytes (5, 6, 7, 8).
The expression of ICAM-1 can be up-regulated by inflammatory cytokines,
such as interferon- (IFN-), interleukin-1ß (IL-1ß), and tumor
necrosis factor-
(TNF-), depending on the tissue (6, 8, 9, 10). The increased ICAM-1 expression on the cells is directly
correlated with the LFA-1-dependent adhesion to lymphocytes (11).
ICAM-1/LFA binding seems to be critical for the interaction between
immune cells and the opposing target cells in many immunological
processes, including organ specific diseases.
It has also been reported that ICAM-1 was highly expressed on thyrocytes, as well as on capillary and postcapillary vascular endothelial cells in GD thyroid, but not in non-GD thyroid (6, 8, 12, 13, 14). The binding of ICAM-1/LFA-1 seems to be involved in the migration of lymphocytes in the thyroid gland, as well as the interaction between lymphocytes and thyrocytes in GD. The infiltrated T cells are activated by thyrocytes through the cellular adhesion in both an antigen-dependent and independent manner, which leads to AITD (15, 16). Thus, ICAM-1 is implicated to play an important role in GD thyroiditis. However, it still remains to be elucidated whether T cell LFA-1 and its ligand ICAM-1 on thyrocytes have functional consequences for thyrocytes, which are relevant to the pathogenesis of GD. In the present study, we focused our attention on regulating the thyrocyte function by the cellular adhesion of thyrocytes to lymphocytes infiltrating into the Graves thyroid. Our in vitro study demonstrated that the proliferation of GD-thyrocytes was induced by cellular adhesion to infiltrated lymphocytes via the ICAM-1/LFA-1 pathway, independent of cytokines.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thyroid tissues were obtained by subtotal thyroidectomy from 25 patients with GD who had been treated with an antithyroid drug and iodine. The thyrocytes were isolated as described previously (17). After the tissues were rinsed in PBS with penicillin (100 U/mL) and streptomycin (100 µg/mL), connective tissue was removed, and thyroid tissue was finely minced. The obtained thyroid tissue fragments were stirred in flasks containing 100 µg/mL collagenase (Sigma, St. Louis, MO) and 3.33 mg/mL dispase (Godo Shusei, Tokyo, Japan) in HBSS, on a magnetic stirrer, at 37 C for 30 min. The suspension was passed through a nylon filter and mixed with RPMI-1640 containing 10% heat-inactivated FCS. The filtrate was centrifuged at 1000 rpm for 5 min, and pellets were defined as thyrocytes.
Separation of mononuclear cells
The method used to prepare mononuclear cell fractions of thyroid tissues and peripheral blood have been previously described (15). Human peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Conray (Daiichi Pharmaceutical Company Ltd., Tokyo, Japan) gradient centrifugation from heparinized peripheral blood. Infiltrated mononuclear cells in the thyroid gland were obtained from thyroid tissues from 25 patients with GD (15). The cell suspension isolated by mechanical disaggregation of thyroid tissues was purified by density gradient centrifugation. PBMC, and intrathyroidal mononuclear cells (ITMC) were washed 3 times with PBS solution and were treated with potassium cyanide to exclude contaminated erythrocytes.
Cell culture
The thyrocytes were plated on 250-mL culture flasks in PRMI-1640 containing 10% FCS and were cultured at 37 C in a humidified atmosphere of 5% CO2 in air for 3–4 days, and the medium was changed every day until a monolayer was obtained. Then, the thyrocytes were detached from the culture flasks by adding trypsin-EDTA solution, and the cells were used for various experiments. To evaluate changes in ICAM-1 expression and cellular adhesion, the cultured cells were also examined after more than 7 days.
Flow microfluorometry
Purified GD-thyrocytes, normal PBMC, GD-PBMC and GD-ITMC
were stained with several monoclonal antibodies (mAbs). Staining
and flow cytometric analysis were carried out by standard procedures,
as described (18, 19). The mononuclear cells were prestimulated with 10
ng phorbol myriacetate (PMA, Sigma), which is a
pharmacological integrin-trigger, for 15 min. The cells (5 x
104) were incubated with anti-ICAM-1 (CD54) mAb
84H10 (Fujisawa Pharmaceutical Co., Osaka, Japan), LFA-1 (CD11a)
mAb TS1/22 (Fujisawa), activated LFA-1 mAb NKI-L16 (C. Figdor,
Nijmegen, Netherlands) (20), or control mAb thy1.2 (Fujisawa) in FACS
media consisting of HBSS, 0.5% human serum albumin (Green Cross,
Osaka, Japan), and 0.2% NaN (Sigma) for 30 min at
4 C. After washing the cells with FACS media three times, the cells
were further incubated with fluorescein isothiocyanate
(FITC)-conjugated goat antimouse IgG Ab (Fujisawa) for 30 min at 4 C.
After washing again three times in the same way, the stained cells with
the mAbs were detected using a FACScan (Becton Dickinson and Co., Mountain View, CA). GD-thyrocytes (2 x
104) were cultured for 24 h in a 96-well
cultured plate (Becton Dickinson and Co., Franklin Lakes,
NJ) and further incubated with or without 10 ng/mL IL-1ßor 100 U/mL
IFN- for 24 h. Then, the ICAM-1 expression on GD-thyrocytes was
stained using anti-ICAM-1 (CD54) mAb 84H10 (Fujisawa). Amplification of
the mAb-binding was provided by a 3-decade logarithmic amplifier.
Adhesion assay
Adhesion assay was performed essentially as previously described
(21, 22). Purified thyrocytes (2 x 104) in
RPMI-1640 with 10% FCS were applied to 96-well culture plates
(Becton Dickinson and Co., Franklin Lakes, NJ) and were
cultured for 24 h. Then thyrocytes were treated with or without 10
ng/mL IL-1ß or 100 U/mL IFN- for 24 h. Mononuclear cells were
labeled with the fluorescent dye BCECF-AM
(Calbiochem-Nobabiochem Co., San Diego, CA) for 30 min,
were washed twice with PBS, and were resuspended in RPMI1640 containing
0.1% heat-denatured BSA. After the plates were washed three
times with PBS, the labeled mononuclear cells (2 x
104) in RPMI1640 with 10% FCS were added to the
culture with or without relevant adhesion-blocking mAbs in the presence
of 10 ng/mL PMA, a pharmacological relevant trigger for
integrin-adhesives. After a setting period of 30 min at 4 C, which
allowed mAb binding, the plates were rapidly warmed to 37 C for 30 min.
Then, the plates were gently washed twice with RPMI-1640 at room
temperature to remove completely nonadherent mononuclear cells and were
monitored by visual inspection using a microscope. All mAbs were used
at a saturating concentration of 10 µg/mL, which was shown in
previous studies to maximally inhibit the relevant adhesive
interaction. The mononuclear cells that remained attached to the plates
were analyzed using a Fluorescence Concentration Analyzer
(Dynatech Corp., Chantilly, VA). After subtraction of the
background cells binding to uncoated wells, the percentage of bound
cells to total cells was calculated. Background binding was less than
3% of the total. Data are expressed as mean percentage ±
SD of cells binding.
Assessment of cell proliferation
Cell proliferation was evaluated by a cell proliferation reagent
WST-1 kit (Roche Molecular Biochemicals, Tokyo, Japan).
This assay is based on the cleavage of the tetrazolium salt WST-1 by
mitochondrial dehydrogenase in viable cells. An expansion in the number
of viable cells results in an increase in the overall activity of
mitochondrial dehydrogenase in the samples (23). WST-1 is more
sensitive for assessment of cell proliferation and does not require
cells to be solubilized. The assay was performed according to the
manufacturer’s guidelines. GD-thyrocytes proliferation by cellular
adhesion to lymphocytes was assessed as follows. GD-thyrocytes were
seeded at a density of 2 x 104 cells/well
to 96-wells tissue culture plates (Becton Dickinson and Co., Franklin Lakes, NJ), in RPMI-1640 containing 10% FCS, for
24 h. After 24 h incubation, ITMC and PBMC, which were fixed
with formaldehyde (1%) for 2 h after pretreatment with or without
PMA (10 ng/mL), were added to the thyrocytes in each well in RPMI-1640
containing 0.2% BSA, in the presence or absence of 10 ng/mL IL-1ß or
100 U/mL IFN-, with or without 10 µg/mL ICAM-1Ab. After being
cultured for 24 h at 37 C, the ready-to-use WST-1 reagent was
added to the cultures and incubated for 1 h at 37 C. The
absorbance at 450 nm, against a reference wave length of 650 nm, was
determined. As blank value, we used the absorbance of the culture
medium containing lymphocytes fixed with formaldehyde. The coefficient
variation within the assay was less than 5%.
In some experiments, DNA synthesis of GD-thyrocytes was also assessed
by [3H]-thymidine incorporation. The cells were
seeded at a density of 1 x 105 cells/well
to 96-well tissue culture plates (Becton Dickinson and Co., Franklin Lakes, NJ) in RPMI-1640 containing 10% FCS, for
24 h. The medium was changed to a serum free medium in the
presence or absence of 10 ng/mL IL-1ß and 100 U/mL IFN-. After
24 h incubation, ITMC and PBMC, which were fixed with formaldehyde
(1%) for 2 h after pretreatment with or without PMA (10 ng/mL),
were added to the thyrocytes in each well in RPMI-1640 containing 0.2%
BSA, in the presence or absence of 10 µg/mL LFA-1Ab. After being
cultured for 48 h at 37 C, [3H]-thymidine
(0.25 mCi/mL) was added to each culture, and they were further
incubated for 8 h at 37 C. The cells were then washed briefly in
PBS twice and dissociated with 0.25% trypsin/0.05 mol/L EDTA solution.
The radioactivity was determined in a liquid scintilation counter
(Aloka lSC-3500E, Aloka Co., Tokyo, Japan).
Statistical analysis
The results were expressed as the mean ± SD. A statistical analysis was carried out by ANOVA. Data on the expression of adhesion molecule were compared using unpaired t test, and those on adhesion assay and proliferation assay were evaluated by paired t test. The given significance levels were determined by Scheffe F-tests and Mann-Whitney U-tests using Stat View-J 4.5 (Macintosh). A P value of less than 0.01 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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on the
cultured thyrocytes of Graves’ patients
Initially, the identification of cell surface adhesion molecules
on cultured thyrocytes obtained from patients with GD was studied (Fig. 1
). The cells were stained with mAbs to
various cell surface molecules and second FITC-labeled antimouse
IgG Ab, and then analyzed by a FACScan. All of the thyrocytes obtained
from 10 patients with GD expressed a high amount of ICAM-1, which has
been reported to be absent on thyrocytes in normal thyroid (13, 16).
Treatment with either IL-1ß or IFN- did not augment ICAM-1 on the
thyrocytes when the cells were assayed after 2 days in monolayer
cultures (Fig. 1, Table 1). However, the
quantity of ICAM-1 on the thyrocytes was decreased significantly with
the continuation of monolayer cultures, and IL-1ß or IFN- enhanced
ICAM-1 expression on GD thyrocytes cultured for 6 and 9 days (Fig. 1, Table 1). The following experiments were performed using GD-thyrocytes
cultured for 2 days.
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We performed comparative studies on the expression of adhesion
molecules among normal PBMC, GD-PBMC, and GD-ITMC. LFA-1, one of the
major receptor for ICAM-1, was expressed on normal PBMC and GD-PBMC but
was much higher on GD-ITMC from the same patient than normal PBMC,
GD-PBMC, and GD-ITMC. However, the quantity of LFA-1 expression is much
higher on GD-ITMC than normal PBMC and GD-PBMC (Fig. 2, Table 2). Lymphocyte integrins, such as LFA-1,
cannot function until they are activated, and integrin-trigger is
essential to the integrin-mediated adhesion. Of interest is that
GD-ITMC highly expressed activated form of LFA-1 detected by NKI-L16
mAb, which binds to adhesive configuration of LFA-1 (20), compared with
normal PBMC and GD-PBMC (Fig. 2, Table 2). Furthermore, GD-ITMC also
expressed larger amounts of CD69, regarded as activation markers, than
normal PBMC and GD-PBMC, suggesting that GD-ITMC were already activated
enough to possess triggered LFA-1, which is a major receptor for ICAM-1
highly expressed on GD-thyrocytes.
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To clarify whether the adhesion molecules are functional ones, we
assessed the adhesion of normal PBMC, GD-PBMC or GD-ITMC to
GD-thyrocytes by adhesion assay. Normal PBMC or GD-PBMC only scarcely
adhered to thyrocytes; but after the activation with PMA, a
pharmacological trigger for integrin activation, normal PBMC or GD-PBMC
adhered well to GD-thyrocytes (Fig. 3).
Contrarily, GD-ITMC could adhere to GD-thyrocytes either in the
presence of or in the absence of PMA, suggesting that ITMC did not
require any activation stimuli for the functional adhesion. The
bindings of GD-ITMC were inhibited by the addition of ICAM-1 mAb or
LFA-1 mAb. Adhesions of PMA-stimulated PBMC to GD-thyrocyte were also
inhibited by these mAbs (data not shown). The inhibition of cellular
binding by ICAM-1 mAb was in a dose-dependent manner (Figs. 3 and 4). The blocking studies using mAbs
suggest that intrathyroid lymphocytes-thyrocytes adhesion is mainly
mediated by the LFA-1/ICAM-1 adhesion pathway, and GD-ITMC possess the
triggered LFA-1. The PMA-activated PBMC or GD-ITMC binding to the
thyrocytes was not modulated by pretreatment with IL-1ß or IFN-
for 24 h (Fig. 5), which may reflect
on the results of ICAM-1 expressions on GD-thyrocytes, as shown in Fig. 1
. After 6 days in monolayer culture, the binding of GD-thyrocytes and
GD-ITMC was enhanced by IL-1ß and IFN- (Fig. 6).
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Finally, we examined whether the proliferation of thyrocyte is
regulated by the cellular adhesion of lymphocytes to the thyrocytes
through the ICAM-1/LFA-1 pathway. The cellular adhesion of lymphocytes
to GD-thyrocyte induces the proliferation of thyrocytes. Proliferation
of GD-thyrocytes was assessed by the WST-1 test described in
Materials and Methods. In these experiments, lymphocytes
(pretreated with or without PMA) was fixed by 1% formaldehyde and then
added to GD-thyrocyte monolayers. The proliferation of GD-thyrocytes
was stimulated by the addition of the fixed PMA-activated PBMC or ITMC
but not changed by the addition of the fixed normal PBMC (Fig. 7). The PMA-activated PBMC or
GD-ITMC-induced GD-thyrocyte proliferation was inhibited by the
addition of anti-ICAM-1 mAb. We also assessed
[3H]-thymidine incorporation of GD-thyrocytes
by cellular interaction through ICAM-1/LFA-1, and the DNA synthesis was
also stimulated by the binding (data not shown). These results suggest
that the proliferation of GD-thyrocytes is mediated by the LFA-1/ICAM-1
adhesion pathway.
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). IFN- rather reduced the WST-1 of
the thyrocytes, but the addition of the fixed PMA-activated PBMC and
GD-ITMC increased it to the levels of control cultured thyrocytes (Fig. 8B). These lymphocyte-dependent cell proliferations were also inhibited
by the addition of anti-ICAM-1 mAb. These results suggest that
thyrocyte proliferation by cellular adhesion to lymphocyte is
independent of that of IL-1ß and IFN-.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In contrast with LFA-1, which is restricted to lymphocytes, ICAM-1 can be expressed on a wide variety of cells, and its induction in inflammation is an important means of regulating ICAM-1/LFA-1 interaction (5, 27, 28). In this study, ICAM-1 was highly expressed on cultured GD-thyrocytes, and the GD-thyrocytes adhered to ITMC through the ICAM-1/LFA-1 pathway. Conflicting results have been published on ICAM-1 expression on GD-thyrocytes; some groups have shown that ICAM-1 is expressed on GD-thyrocytes (9, 13, 14), whereas others have failed to detect ICAM-1 (9, 12, 13). Arreaza et al. (14) showed that the expression of ICAM-1 and HLA-DR can be detected in cultured GD-thyrocytes of early phase and then reduced gradually to the level of normal thyrocytes while the culture continued. We observed the reduction of ICAM-1 expression on GD-thyrocytes when the assays were performed using the cells cultured for more than 7 days. The disagreement of ICAM-1 expression on cultured GD-thyrocytes could be derived, in part, from methodological differences.
Interesting findings were observed in the expression of LFA-1 on GD-ITMC. The majority of ITMC was CD3+ T cells (data not shown); and to simplify the experimental system, we used ITMC as thyroid gland-infiltrating T cells. ITMC expressed remarkably higher amounts of LFA-1 than normal PBMC or GD-PBMC. Integrins such as LFA-1 cannot adhere to their ligands until triggered to be an active configuration (18, 19). ITMC expressed markedly a high quantity of activated form of LFA-1, whereas PBMC from normal and GD donors scarcely did. Interaction of T cell receptors with cells bearing specific antigen generates intracellular signals that leads to the conversion of LFA-1 to a high-avidity state and regulates ICAM-1/LFA-1-dependent adhesion in an antigen-specific manner (5, 11).
LFA-1 binds to ICAM-1, strengthening the interaction between cells bearing LFA-1 and those expressing ICAM-1 (6). GD-ITMC spontaneously adhered to GD-thyrocytes without stimulation by PMA, which is the strongest pharmacological integrin-trigger, whereas PBMC adhered to thyrocytes only in the presence of PMA. Furthermore, the adhesions of GD-ITMC to GD-thyrocytes were largely inhibited by anti-ICAM-1 mAb and/or anti-LFA-1 mAb, indicating that the adhesions of GD-ITMC to GD-thyrocytes are mediated by the LFA-1/ICAM-1 pathway. The cellular adhesion of GD-thyrocytes to ITMC or PMA-stimulated PBMC induced the proliferation of GD-thyrocytes. Blocking experiments showed that LFA-1/ICAM-1 adhesion is involved in the GD-thyrocyte proliferation. Because GD is a characteristic AITD where thyrocytes proliferate well, the cellular interaction by LFA-1/ICAM-1 may be involved, in part, in the development of a goiter in GD. To our knowledge, this is the first report to indicate that infiltrating lymphocytes in the thyroid stimulate the proliferation of thyrocytes by lymphocyte-thyrocytes cellular adhesion through the LFA-1/ICAM-1 pathway.
Cytokines act, in a paracrine fashion, as soluble factors between cells
and have an important role in the autoimmune response. Activated
T-cells in the thyroid gland of AITD disease secrete a variety of
cytokines, including IFN-, IL-1ß and TNF-, all of which
influence neighboring thyrocytes (1, 29, 30, 31). These cytokines cause
induction of ICAM-1 expression in a wide variety of tissues, resulting
in an increase in binding to lymphocytes through their surface LFA-1
(5, 6, 8, 9, 10, 11, 27, 32). The expression of ICAM-1 on normal and
GD-thyrocytes has also been enhanced by these inflammatory cytokines
(8, 33, 34). The present study showed that, in GD-thyrocytes cultured
for 2 days, IL-1ß and IFN- did not constantly up-regulate ICAM-1
expression and binding of GD-thyrocytes to ITMC through ICAM-1/LFA-1.
However, ICAM-1 expression on GD-thyrocytes and its binding to LFA-1 on
ITMC were enhanced by IFN- and IL-1ß when the assays were done
using the cells cultured for more than 7 days. It is suggested that
these immunomodulators may play a prime role in ICAM-1 expression on
thyrocytes (6, 8, 35). We also observed a high expression of F-actin in
the cell cortex and marked spreading and polymerization of F-actin in
2-day-cultured GD thyrocytes, which were decreased by continuation of
the culture (data not shown). GD-thyrocytes of the early culture phase
may be maximally stimulated with cytokines produced by ITMC in
vivo and ITMC contaminated in the cultures of the early phase
(36). In a previous study of GD-thyroid xerografts in animals, ICAM-1
on thyrocytes was dramatically reduced in the nude mice xerograft, and
maintained in the SCID mice, but reduced when the SCID mice were
treated with an anti-CD4+ T cell agent (14). Furthermore, ICAM-1 on the
thyrocytes in nude mice was enhanced by IFN- and TNF-. These
results, taken together, suggest that ICAM-1 expression depends on the
presence of lymphocytes and the secretion of stimulatory cytokines. The
cytokines produced by T-cells may enhance the expression of ICAM-1 on
thyrocytes, leading to a corresponding increase in the adhesive
properties of lymphocyte (11).
It has been suggested that IL-1ß stimulates growth of the rat FRTL5
rat thyroid cell line and GD-thyrocytes (37, 38), and IFN- inhibits
that of GD-thyrocytes (39). Our study showed that the proliferation of
GD-thyrocytes was stimulated by IL-1ß and inhibited by IFN-. Of
interest was that the cellular adhesion of GD-thyrocytes to ITMC or
PMA-activated PBMC via ICAM-1/LFA-1 induced GD-thyrocyte proliferation
independent of the proliferative response of IL-1ß and IFN-. The
growth effect by the cellular binding was additive to that of IL-1ß
and overcame the inhibitory effect of IFN-. Also, the cytokines
produced from T-cells in GD-thyroid may be involved in thyroid
cell growth not only by direct action but also by indirect action via
ICAM-1/LFA-1 binding derived from modulating the expression of adhesion
molecules. We thereby propose that T cells infiltrating in the GD
thyroid gland plays an important role in the pathogenesis of AITD that
is associated with sequential events in T cell-thyrocytes cellular
interaction through the LFA-1/ICAM-1 pathway, thus increasing the
proliferation of GD-thyrocytes.
Autoantibodies to TSH receptor (TRAb) play a direct pathogenetic role in AITD. Two major categories of TRAb have been identified. Thyroid-stimulating antibody (TSAb) is a cause of hyperthyroidism in GD, and thyroid-blocking antibody (TBAb) inhibits the biological action of TSH and TSAb, leading to hypothyroidism. TSAb promotes the growth of thyroid follicular cells via adenylate cyclase similar to TSH (40, 41). Because no assay system to evaluate the effect of TSAb on the proliferation of GD- thyrocytes is available at present, it is difficult to compare the growth promoting potency of TSAb with that via the cellular adhesion observed in this study. The autoantibodies may be involved in goiter development; however, experience accumulated from clinical practice suggests that no correlation is observed between the goiter size and the autoantibodies in GD. In this study, there was no correlation among the goiter size, TRAb, thyroid peroxidase antibody, thyroglobulin antibody, and expression of the adhesion molecules (data not shown). The pathogenesis of the goiter in patients with GD may involve cellular hyperplasia, cellular hypertropy, increased blood flow within the gland, and lymphocytic infiltration (42); and these multiple factors are associated with the goiter development. Also, no correlation was observed between the expression of the adhesion molecules, adhesion assay data, and proliferation assay data (data not shown). Although the autoantibodies may be a major causal factor for goiter development in GD, the cellular adhesion of infiltrating lymphocytes to thyrocytes via LFA-1/ICAM-1 may be, in part, involved in the development of the goiter.
In conclusion, our data indicated that LFA-1 expressed on GD-ITMC became an adhesive configuration, GD-thyrocytes possessed a high quantity of ICAM-1, GD-ITMC remarkably adhered to GD-thyrocytes through the LFA-1/ICAM-1 pathway, and its adhesion induced the proliferation of GD-thyrocytes independent of cytokines locally produced.
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Acknowledgments |
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Footnotes |
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Received May 26, 1999.
Revised August 30, 1999.
Accepted October 14, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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4 subunit of the integrin
VLA-4:distinct effects on adhesion to CS1/fibronectin, VCAM-1, and
invasion. J Cell Biol. 123:245–253. inhibition of human thyrotropin receptor gene
expression. J Clin Endocrinol Metab. 77:1084–1089.[Abstract]
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