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Institute of Anatomy and Cell Biology, Göteborg University, Medicinaregatan 3, S-413 90 Göteborg, Sweden
Address all correspondence and requests for reprints to: Dr. Ragnar Ekholm, Institute of Anatomy and Cell Biology, Göteborg University, Medicinaregatan 3, S-413 90 Göteborg, Sweden. E-mail: Ulla.Bjorkman{at}anatcell.gu.se
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Abstract |
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In conclusion, iodine binding in filter-cultured thyroid epithelium under normal conditions is an extracellular process located at the cell surface. When H2O2 is available intracellularly, iodination takes place in the cytoplasm, evidently catalyzed by intracellular thyroperoxidase. Normally, this iodination is prevented by cytosolic GSH peroxidase that effectively degrades H2O2 and thus controls intracellular iodination. The observations should be applicable to the thyroid in vivo.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The paper presents an autoradiographic study with 125I on porcine thyroid epithelia grown on a porous filter in a bicameral culture chamber, a system described by Chambard and her colleagues (4, 5). In this system, the thyroid cells form a monolayer that separates the apical and basal compartments of the chamber. The monolayer is electrically tight (6, 7, 8), and the cells are structurally polarized (9). Functional polarity is also evident: TSH receptors are confined to the basolateral surface (4); iodide uptake occurs at the basolateral surface (4, 9), whereas iodide efflux is restricted to the apical surface (9); thyroglobulin secretion is mainly directed apically (4, 10). Thus, the physiological qualities of the filter-cultured epithelium are well documented. However, as regards the site(s) of iodine organification the opinions diverge. Gruffat et al. (11) measured the radioiodinated Tg in the apical and basal compartments over several days and concluded that Tg was iodinated only in the apical compartment. On the other hand, in similar experiments Kuliawat and Arvan (12) demonstrated iodinated Tg both in the apical compartment and in lysates of the epithelium and inferred that iodination takes place both in the apical compartment and intracellularly.
The first part of the present study is the basis for the following sections and comprises an examination of the autoradiographic distribution of bound radioiodine at varying times after 125I administration in filter epithelium grown under normal culturing conditions. The second part is a study of the effects on the autoradiographic labeling pattern of addition of H2O2 at varying concentrations to the basal compartment. The third part deals with the effect of GSH peroxidase on the 125I labeling in the cultures. GSH peroxidase constitutes, together with catalase, the primary defense system against H2O2 in most cells (13). The thyroid has a cytosolic selenium-containing GSH peroxidase (14, 15, 16), and H2O2 scavenging is an essential physiological mechanism in the thyroid (16, 17, 18). Observations on rats (19) have suggested that reduced selenium supply, leading to decreased GSH peroxidase activity, increases the H2O2 level and thus the activity of TPO and hormone synthesis. Selenium deficiency is accompanied by low serum GSH peroxidase in myxedematous cretins in endemic goitre (20, 21, 22), and it has been proposed that reduction of GSH peroxidase activity and increased H2O2 concentration in the thyroid could damage the gland and be a factor in the patho-physiology of myxedematous cretinism (23, 24). A recent study on thyroid cell cultures in our laboratory (16) showed an effective degradation by GSH peroxidase of H2O2 at a concentration of 100 µM and below (at higher concentrations of H2O2, the degradation was dominated by catalase).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Labeling with 125I
In the culture chambers to be used in the experiments, the
culture medium in both compartments was replaced by Eagle’s MEM
without phenol red (which is an inhibitor of thyroglobulin iodination,
26). After two changes of this medium, the cultures were preincubated
for 30 min in the medium to be used in the labeling, i.e.
Eagle’s MEM without serum or with 0.5% FCS. Labeling was started by
adding 125I to the basal compartment, usually 50–100
µCi. This radioactivity of carrier-free 125I corresponds
to an iodide concentration of 0.05–0.1 µM, a
concentration considered to be within the physiological range. When
catalase was used, it was added to the apical or basal compartment or
both compartments approximately 15 min before the addition of
radioiodide. Catalase, dialyzed against 0.9% NaCl overnight, was added
to a final concentration of 0.01%. Methimazole (MMI) was used as an
inhibitor of thyroperoxidase at a final concentration of 2
mM; it was added to the basal compartment. Incubation with
radioiodide was for 15 min to 3 h and was performed at 37 C in
humidified atmosphere with 5% CO2.
Preparation of autoradiographs
The incubation with 125I was stopped by washing the
chamber inserts with the cultures in several changes of incubation
medium containing 10-7 M KI and 2
mM MMI. The inserts were transferred to the fixative,
either 2.5% glutaraldehyde in Na-cacodylate or a modified Karnovsky
fixative (containing 1% paraformaldehyde and 2.5% glutaraldehyde).
After fixation for 30 min the inserts were washed in sodium cacodylate
and transferred to 0.5% osmium tetroxide in sodium cacodylate for 30
min. After dehydration in ethanol the filter + epithelium specimen was
embedded in Epon in situ. Thin sections were stained with
uranyl acetate and lead citrate and covered with carbon. The
autoradiographic emulsion (Ilford L4) was applied onto the grids with
the loop technique. After appropriate exposure, the autoradiographs
were developed in Kodak D19 for 1.5 min and fixed in Kodak acid fixer
for 2 min.
Separation of 125I-labeled proteins on SDS-PAGE
Cultures to be used for analysis of their contents of labeled
proteins were washed twice with Eagle’s MEM without phenol red. The
incubation was performed in the same medium at 37 C for 1 h and
was started by adding 20 µCi 125I- +
10-7 M KI to the basal compartment. When MMI
was used as an inhibitor of thyroperoxidase, it was added to the basal
medium at a concentration of 2 mM. The incubation was
stopped by sucking off the medium in both compartments and washing the
epithelium on the filter carefully with PBS, pH 7.2, containing 2
mM MMI, protease inhibitors (Pefabloc, leupeptin,
aprotenin) and 10-7 M Kl. The filter was cut
out from its chamber insert and lysed in 100 µl of sample buffer (0.5
M Tris-HCl buffer, pH 6.8, containing 10% glycerol, 2%
sodium dodecyl sulfate and 5% 2-mercaptoethanol). SDS-PAGE was
performed according to Laemmli (27) on a 7.5% polyacrylamide gel.
Autoradiographs from the gels were prepared with Amersham’s Hyperfilm
MP.
Cultures to be used for analysis of labeled proteins in the apical and basal medium were washed and incubated with 10 µCi 125I + 10-7 M KI, added to be basal medium, for 24 h. After incubation, the apical and basal media were sucked off and diluted to 1 ml with PBS, pH 7.2, containing 2 mM MMI, 10-7 M KI, and protease inhibitors as above. After concentration in microconcentrators (Amicon, Inc., Beverly, MA), sample buffer was added and SDS-PAGE was performed as above.
Immunoblot analysis
Proteins separated by PAGE were transferred electrophoretically
from the gel to a nitrocellulose membrane. Transfer was carried out at
room temperature for 3 h at 70 V using a Bio-Rad mini transblot
apparatus. Antithyroglobulin immunoglobulin, obtained from rabbits, was
used as primary antibody, and the Enhanced Chemiluminescence Western
Blotting detection system (Amersham), a system using horseradish
peroxidase-conjugated secondary antibody, was used for detection of
thyroglobulin.
Measurement of GSH peroxidase activity
Pig thyroid follicle fragments were prepared as described above
and seeded in 100-mm plastic culture dishes. They were grown to
confluence in 6H medium (see above) containing 5% calf serum and then
cultured for another 6 days in the same 6H medium with 5% serum
(control) or in 6H + 0.5% serum, 6H + 0.5% serum + 0.01
µM selenite, or 6H + 0.5% serum + 0.1 µM
selenite. The cultures were loosened from the dishes by brief
incubation in Ca2+ and Mg2+-free HBSS
containing collagenase (20 U/ml), trypsin (0.75 mg/ml),
heat-inactivated dialyzed chicken serum (2%), and 2 mM
EGTA. After washing in regular incubation medium, the cells were
resuspended in 100 mM Tris-HCl buffer (pH 7.4), containing
5 mM EDTA. The cell suspension was sonicated for 3 x
15 sec in an ice bath, an aliquot was withdrawn for DNA determination
and the rest of the homogenate was centrifuged at 20,000 x
g for 2 h; the supernatant was used for enzyme
analyses.
GSH peroxidase activity was assayed by a modificiation of the method of Paglia and Valentine (28) using tertiary butylhydroperoxide as the substrate. Varying volumes of the sample supernatant were diluted with 100 mM Tris-HCl buffer (pH 7.4) and added to the incubation mixture which in a final volume of 1 ml contained 5 mM EDTA, 0.134 mM NADPH, 2 mM reduced glutathione, and 1 U/ml glutathione reductase; in some incubations, the medium contained 1 mM Na azide. The reaction was performed at 37 C in a Zeiss PMQ III spectrophotometer. The oxidation of NADPH was registered at 340 nm for several minutes before 0.16 mM tertiary butylhydroperoxide was added and the registration continued. The activity of GSH peroxidase was expressed as nmol of NADPH oxidized per min per mg DNA; this was equivalent to nmol H2O2 oxidized per min per mg DNA. Determination of DNA was performed with a fluorescence assay (29).
The oxidation rate of NADPH before the addition of tertiary
butylhydroperoxide was low (
A340/min 
0.006)
compared with the oxidation after addition of tertiary
butylhydroperoxide ( A340/min = 0.050–0.150). The
same results were obtained when tertiary butylhydroperoxide was added
before the test sample.
Chemicals
Collagenase (type II) was obtained from Worthington Biochemical
Corporation (Freehold, NJ); Eagle’s MEM, FCS, and calf serum were
purchased from Life Technologies Ltd. (Paisley, UK); Coon’s modified
Ham’s F-12 medium, TSH (bovine), insulin, hydrocortisone, human
transferrin, somatostatin,
glyceryl-L-histidyl-L-lysine acetate,
methimazole, glutathione reductase, leupeptin, aprotenin and sodium
selenite were obtained from Sigma Chemical Co. (St. Louis, MO);
[125I] sodium iodide and Hyperfilm MP were from Amersham
Life Science (Buckinghamshire, UK); catalase (65,000 U/mg) from beef
liver and 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride
(Pefabloc) were obtained from Boehringer Mannheim Scandinavia (Bromma,
Sweden); methimazole was from Merck (Darmstadt, Germany).
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Results |
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125I-labeling of thyroid epithelium cultured with
standard methods
The pattern of distribution of silver grains in the
autoradiographs of sections of control cultures was essentially the
same after incubation with 125I for periods of 15 min to
3 h. The pattern was similar in autoradiographs from specimens
incubated with radioiodide in the presence and absence of serum
proteins in the incubation medium and was not principally influenced by
the exposure time of the autoradiographs. Addition of 0.1
µM carrier iodide or 2 mM perchlorate did not
essentially change the labeling pattern. Grains were regularly
concentrated along the apical cell surface, in near association with
the apical plasma membrane (Fig. 1
). Grains were also
always accumulated along the basolateral surface and were likewise
closely related to the plasma membrane. The lateral row of grains was
continuous with the basal grains and could be followed from the basal
surface up to the junctional complex. Accumulation of silver grains was
also present over narrow and widened intercellular spaces (Fig. 2). The latter were most frequent and largest in
multilayered parts of the epithelium. The plasma membranes bordering a
widened space, and belonging to two or several cells, could all be
smooth or furnished with microvilli or a mixture of these membrane
types. The spaces were labeled faintly or heavily; in the former case,
the silver grains were generally located marginally. Furthermore,
grains always occurred over the filter forming a concentration gradient
declining from the basal cell surface.
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).
Counting of approximately 1,000 grains in 25 autoradiographs from 5
control cultures labeled for 1 h showed that the number of
cytoplasmic grains was about 10% of the grains associated with the
plasma membrane (apical + basolateral) of the same cell. About half the
number of these grains were found over the supranuclear region and the
remaining grains scattered over the rest of the cytoplasm.
The autoradiographic pattern described above was changed by
adding catalase to the apical or basal compartment. By this procedure,
iodination could be inhibited by degradation of
H2O2 on one or the other side of the epithelium
since catalase does not pass the plasma membrane. Adding catalase to
the apical compartment resulted in a virtually complete inhibition of
the autoradiographic reaction associated with the apical plasma
membrane and grains over the supranuclear region of the cells were rare
(Fig. 3). The apically added catalase had no appreciable
effect on the labeling at the basolateral surface of the epithelium and
the intercellular spaces. Addition of catalase to the basal compartment
caused an almost complete inhibition of the labeling associated with
the basolateral domain of the plasma membrane and the intercellular
spaces; however, an occasional widening of the intercellular space
remained labeled, probably because it was shut off from the basal
epithelial surface and not reached by the catalase. Basally added
catalase did not influence the labeling at the apical cell surface.
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125I-labeling of thyroid epithelium in media
containing H2O2
Incubation of epithelium, cultured under standard conditions, for
1 h in the presence of H2O2 at
concentrations of 0.1, 1, and 10 µM had no noticeable
influence on the structure of the epithelium; at 100 µM
H2O2 indications of some deterioration of the
cells (e.g. vacuolization of the cytoplasm) were
observed.
Autoradiographs from normal cultures (grown with 5% serum) incubated
with 125I for 1 h in media containing 0.1 or 1
µM H2O2 did not differ
appreciably from those seen after incubation without added
H2O2 (Fig. 1); in both categories of culture,
the labeling was characterized by accumulation of grains along the cell
surfaces and very few grains over the cytoplasm. In contrast,
125I incubation of the same normal cultures with 10
µM H2O2 resulted in fundamentally
different autoradiographs (Fig. 4): the silver grains
were distributed over the entire cytoplasm, apparently without any
local concentrations. The nucleus was devoid of labeling. No
accumulations of grains (only scattered grains) were present along the
apical and basolateral cell surfaces.
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125I-labeling of epithelium with low and high activity
of GSH peroxidase in media with and without
H2O2
To lower the GSH peroxidase activity in the epithelium, the cells
were cultured in medium with reduced selenium content that was achieved
by decreasing the serum concentration (from 5%–0.5%).
To elevate the GSH peroxidase activity, the cells were grown in medium
supplemented with 0.01 or 0.1 µM selenite (and containing
5% or 0.5% serum). As shown in Table 1, addition of
0.01 µM selenite to the culture medium containing 0.5%
serum resulted in a GSH peroxidase activity of the same order as that
in 5% serum, whereas 0.1 µM selenite had a drastic
effect on the enzyme activity. Neither the reduction of the serum
concentration nor the supplementation with selenite had any appreciable
effect on the electron microscopical structure of the epithelium.
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and Table 2).
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and Table 2).
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) of the labeled proteins extracted from
epithelia incubated for 1 h with 125I in the absence
of H2O2 and in the presence of 10 and 100
µM H2O2 all showed a distinct and
dominating band in the 330-kDa region (estimated by mol mass standards
not visible in the autoradiographs); this band was identified as Tg
with immunoblot analysis. In the gels from cultures incubated with
H2O2 several bands of smaller proteins were
much more densely labeled in the H2O2 specimens
than in the control; some of these bands reacted with anti-Tg
antibodies.
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) of the labeled proteins in the apical
medium after incubation with 125I for 24 h showed a
dominating Tg band; this band was hardly visible in the basal
medium.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One may ask whether the labeled protein was bound to 125I at the sites where it appeared in the autoradiographs or if it was labeled intracellularly and transported to these extracellular loci. The latter alternative appears unlikely considering the substantial extracellular labeling already at 15 min incubation and the very low intracellular labeling at all incubation times. Furthermore, light and electron microscopical studies in vivo and in vitro have demonstrated autoradiographic labeling at the cell surface (without intracellular labeling) within seconds and min after radioiodide administration (3, 30, 31). There is no reason to doubt, therefore, that the concentration of autoradiographic grains over extracellular sites observed in the present study represent extracellular iodine binding.
The concentration of grains observed here along the apical cell surface is in accordance with previous autoradiographic studies in vivo and in vitro (3, 30, 31). Concentration of grains along the basolateral cell surface was not expected because of the generally accepted view that the basolateral plasma membrane domain does not carry TPO. However, the possible interpretation that the basolateral grains represent artifacts is contradicted by the fact that the basolateral labeling was almost completely inhibited by catalase added to the basal compartment and by exposure to methimazole. These observations indicate that the basolateral labeling was the result of a TPO-catalyzed reaction. The wide distribution of the iodination capacity favors the notion that the plasma membrane enzymes involved in iodination, TPO and the H2O2 generating enzyme complex, have a distribution in the plasma membrane domains of filter-cultured epithelium that differs from that in vivo. Although the filter-cultures have a well preserved normal structural polarity, it cannot be excluded that a limited reduction of the precision in the sorting of plasma membrane enzymes may occur without patent effect on structural polarity. This suggestion is in line with a recent observation by Kuliawat et al. (32) indicating that TPO, at a low concentration, is present in the basolateral plasma membrane of filter-grown thyroid epithelium.
Contrary to the present conclusion that iodination in filter-cultured thyroid epithelium (under normal culturing conditions) is an extracellular process, Kuliawat and Arvan (12) recently presented the opinion that an important part of the Tg iodination in filter-cultured thyroid epithelium occurs intracellularly. However, this opinion was based on determination of 125I-labeled Tg in lysates of the complete epithelium including the filter and, evidently, all labeled Tg in the lysates was judged to be of intracellular origin. Because the procedures of culturing and labeling used by these authors seem to be similar to those in the present study, we suggest that most of the labeled Tg in the lysates was in fact extracellular.
The present autoradiographic observations per se do not exclude the possibility of a minor intracellular iodination as a few autoradiographic grains were generally located over the cytoplasm. However, some of these grains may represent labeled material endocytosed from the medium in the apical compartment of the culturing chamber, whereas others may represent unspecific and background labeling. It should be pointed out that at short times after 125I-labeling in vivo, the cytoplasm is virtually completely devoid of label even when the grain density over the follicle lumen is extremely high (31). Thus, it appears that the 125I-labeling in the cytoplasm under physiological conditions is insignificant.
It was shown that addition of catalase to the apical compartment reduced the total counts of bound 125I in the epithelia by 20%, whereas catalase in the basal compartment caused a reduction by 60%. These figures agree well with the effects of catalase on the autoradiographs. Catalase in the apical chamber inhibited only the appearance of grains associated with the apical cell surface, whereas catalase in the basal compartment inhibited the induction of grains associated with the (large) basolateral plasma membrane and the grains accumulating over the intercellular spaces (some of which were of considerable width). It should be emphasized in this connection that the difference between apical and basolateral labeling does not give any indication of the iodination capacity at the apical and basolateral plasma membrane. The bound radioiodine at the apical surface in the autoradiographs represents only a small part of the material iodinated at this surface during the radioiodide incubation because most of this material had moved into the medium of the apical chamber before the fixation of the tissue. This is borne out by the analysis of the labeled proteins in the apical and basal media that showed that the labeled material (including Tg) in the basal medium was only a fraction of that in the apical medium.
Gel electrophoresis of the proteins extracted from the epithelium showed that a substantial part of the labeled proteins was Tg. However, the electron microscopic autoradiographs do not discriminate labeled Tg from other labeled proteins. Nevertheless, as it is demonstrated in the present and earlier studies (11, 12) that Tg is iodinated at the apical surface of filter-grown thyroid epithelium, we may assume that at least part of the apical labeling observed in the present study represents Tg. Furthermore, inhibition of iodination by catalase in the apical compartment was found to reduce the total labeling by only 20%, which indicates that the apical autoradiographic labeling cannot represent all labeled Tg in the epithelium. Consequently, labeled Tg should also be a part of the labeled material in the intercellular spaces in the basal region of the epithelium.
The second part of this study showed that addition of H2O2 (at a final concentration of 10 µM) to the standard incubation medium induced intracellular autoradiographic radioiodine labeling. In moderately exposed autoradiographs, the intracellular labeling was scattered over the entire cytoplasm, and no concentrations of autoradiographic grains (only scattered grains) were seen related to the external surface of the plasma membrane. This pattern does not imply that the plasma membrane had lost its iodination capacity but is a consequence of the fact that autoradiography is not a quantitative method in an absolute sense but describes the relative labeling densities in different areas of the tissue section. Thus, increasing the exposure times of the autoradiographs increased not only the density of cytoplasmic grains but also the number of grains at the cell surface. The low labeling at the cell surface compared with that of the cytoplasm in the cultures incubated with 10 µM H2O2 should be related to the distribution of TPO. In these cultures, the H2O2 concentration was high both in the cells and at the cell surfaces. This means that the iodination activities at these sites should mainly be determined by the availability of TPO. It is well documented (2) that TPO is widely spread in the thyroid cells as it is present in the membranes of the RER, Golgi apparatus and transport vesicles as well as the plasma membrane. Considering the great number and dense organization of the cytoplasmic membranes, a much higher autoradiographic labeling over the cytoplasm than over the single plasma membrane should be expected when the availability of H2O2 is not a limiting factor.
The demonstration that intracellular H2O2 is a crucial factor in intracellular iodine binding indicated that the control mechanisms of intracellular H2O2 are of great importance. We have previously shown that thyroid cell cultures possess a very potent H2O2 degradation system involving catalase and GSH peroxidase (16). By varying the selenite concentration in the culture medium, it was possible to change the GSH peroxidase activity. It turned out that low GSH peroxidase activity made the cultures sensitive to H2O2 and incubation with 125I resulted in cytoplasmic labeling even without addition of H2O2. In contrast, high GSH peroxidase activity made the cells resistant to H2O2, and even at 10 µM H2O2 in the incubation medium no cytoplasmic iodine labeling was observed.
Reactive oxygen species, including H2O2, are formed in probably all cell types as by-products in electron transfer reactions. However, the thyrocytes have in addition a physiological production of H2O2, required in the hormone synthesis. The defense against the toxic product must therefore be organized in such a way that it degrades H2O2 without interfering with the physiological iodine binding. The solution of this problem is based on the principle that H2O2 is synthesized at the cell surface, whereas the H2O2-degrading enzymes are located in the cell, in the cytosol (GSH peroxidase) and in peroxisomes (catalase). This organization means that the H2O2 that is formed at the cell surface is immediately involved in the iodination reactions at the same surface and only the excess of H2O2 diffuses into the cells and is degraded; the GSH peroxidase, present in the cytosol, is particularly apt to a prompt attack at this H2O2. Considering that the maximal production of H2O2 in thyroid cell cultures has been found to be approximately 10 nmol·min/mg DNA and the maximal degradation of H2O2 in the order of 30,000 nmol·min/mg DNA (16), it appears that the protection against intracellular iodination should be very efficient.
When the present observations are applied to the normal thyroid follicle, it seems evident that the physiological site of iodination of Tg and hormone synthesis is the apical cell surface and that intracellular iodine binding is unphysiological and normally of minimal importance. This view is based on the facts that, at the apical surface of the epithelium, there are the highest concentrations in the follicle of mature Tg, iodide, and hydrogen peroxide and a large membrane surface (microvillar structure) containing TPO. On the other hand, intracellular iodination is obstructed by the highly effective H2O2 degradation system. Moreover, from a teleological point of view, intracellular iodination should have several drawbacks: a large number of nonthyroglobulin proteins would be iodinated, and the yield of hormones from iodination of intracellular Tg would be poor because most of this Tg is immature. In addition, the hydrolysis of intracellularly iodinated Tg and hormone secretion could not be well controlled as the endocytosis of Tg from the follicle lumen is an important regulatory mechanism in hormone secretion.
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Acknowledgments |
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Footnotes |
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Received December 17, 1996.
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References |
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