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Published online before print November 9, 2004
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,
* Departments of Internal Medicine and
Molecular Microbiology & Immunology, University of Missouri School of Medicine, and
VA Research Service, Columbia, Missouri
1 Correspondence: Division of Immunology & Rheumatology, Dept. of Medicine, University of Missouri, M306 Medical Sciences, One Hospital Dr., Columbia, MO 65212. E-mail: Chenk{at}health.missouri.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(IFN-) inhibit fibrosis, and inflammation eventually resolves. Thyrocyte destruction in wild-type (WT) mice was a result of apoptosis, as many deoxynucleotide triphosphate nick-end labeling + apoptotic thyrocytes were present in these thyroids. The balance of apoptosis and proliferation between thyrocytes and myofbs may be important factors determining the outcome of inflammation to fibrosis versus resolution. Apoptosis and proliferation in thyrocytes versus myofbs were evaluated by dual-staining of cell-proliferating marker (Ki-67) or in situ cell death and cytokeratin or 
-smooth muscle actin and were analyzed by confocal microscopy. Apoptotic and antiapoptotic molecules in G-EAT thyroids were detected by immunostaining. In WT thyroids, which develop fibrosis, only a few myofbs were apoptotic, and many myofbs were Ki-67+, Fas-associated death domain protein-like interleukin-1ß-converting enzyme-like inhibitory protein (FLIP)+, and Bcl-XL+. In contrast, proliferation was predominant on thyrocytes of IFN-–/– mice or anti-TGF-ß-treated WT mice. These results indicate that apoptosis of inflammatory cells and regeneration of thyrocytes in IFN-–/– mice and anti-TGF-ß-treated WT mice may limit development of fibrosis, whereas excessive proliferation of myofbs and loss of thyrocytes in WT mice may contribute to fibrosis.
Key Words: apoptosis • autoimmune inflammation • collagen • autoimmune diseases
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The disruption in thyroid architecture in thyroids that develop fibrosis suggests a perturbation in one of the major mechanisms maintaining homeostasis: proliferation, migration, or apoptosis. Apoptotic cell death is an important mechanism for maintaining homeostasis [7
]. However, apoptosis triggered during inflammation may affect viability of normal tissues and inflammatory cells, thereby altering disease outcome. It is interesting that although G-EAT, induced in DBA/1 wild-type (WT) and interferon- (IFN-)–/– mice, reaches a maximal severity of 4–5+ 19–21 days after cell transfer, two distinct outcomes occur: reduced fibrosis and resolution of inflammation in IFN-–/– thyroids but persistent and progressive fibrosis in WT thyroids [4
]. Attenuation of fibrosis also occurred in thyroids of antitransforming growth factor-ß (anti-TGF-ß)-treated WT mice [6
].
There is an accumulation of myofibroblasts (myofbs) and destruction of thyrocytes in WT thyroids that develop fibrosis [5
]. The loss of thyrocytes may occur as a result of apoptosis in excess of the proliferative response to replace them. Myofbs, which express -smooth muscle actin (-SMA), represent an activated cell phenotype important in fibrosis [8
9
10
11
12
]. Thus, the maintenance of a persistent myofb infiltrate at sites of fibrosis results from a distorted balance among myofb recruitment, proliferation, emigration, and death. Development of fibrosis could be related to an altered response to proliferation and apoptosis-inducing signals. If so, the balance of proliferation versus apoptosis in thyrocytes and myofbs would be altered in WT thyroids that develop fibrosis versus thyroids of IFN-–/– and anti-TGF-ß-treated WT mice, which have decreased fibrosis and resolution of inflammation. This study was undertaken to test the hypothesis that development of thyroid fibrosis may involve an imbalance of proliferation and apoptosis between thyrocytes and myofbs in WT mice. Our results suggest that responses to proliferation and apoptosis-inducing signals between myofbs and thyrocytes may be responsible for development of fibrosis. Studying mechanisms leading to fibrosis versus those resulting in resolution of inflammation and decreased fibrosis may suggest strategies to avoid or reduce excessive fibrosis leading to organ failure in certain autoimmune diseases.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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–/– DBA/1 mice were obtained from Jackson Laboratories (Bar Harbor, ME). Both strains have since been maintained through homozygous breeding in our colonies at the University of Missouri (Columbia). Male and female mice, 7–14 weeks old, were used for these experiments.
Induction of G-EAT and treatment with anti-TGF-ß
Donor WT or IFN–/– DBA/1 mice were immunized twice with 150 µg MTg and 15 ug lipopolysaccharide (LPS; Escherichia coli 0111:B4, Sigma Chemical Co., St. Louis, MO) intravenously (i.v.) at 10-day intervals [2
]. Seven days after the second injection of MTg and LPS, spleen cells were cultured with 25 µg/ml MTg and 5 ng/ml IL-12, as described previously [2
]. After 72 h, cells were harvested, washed, and 3–3.5 x 107 cells were injected i.v. into irradiated (500 Rad) recipient mice. In all experiments, WT donor spleen cells were transferred to WT recipients, and IFN-–/– donor cells were transferred to IFN-–/– recipients [4
]. For anti-TGF-ß1 treatment, WT recipients were given 250 µg anti-TGF-ß1 monoclonal antibody (mAb) 1D11.16.8 [mouse immunoglobulin G (IgG)1; ATCC HB 9849, American Type Culture Collection, Manassas, VA) every 4 days beginning 4 days after cell transfer and at 4-day intervals throughout the experiment [6
]. Recipient thyroids were evaluated for G-EAT 19–21 days later, the time of maximal severity of G-EAT in this adoptive transfer model, or 35–50 days following cell transfer, when G-EAT is resolving in IFN-–/– mice, and fibrosis is maximal in WT mice [2
, 4
].
Evaluation of G-EAT histopathology
Thyroids were removed from 4–5 mice/group at various times after cell transfer, and one lobe of each thyroid was fixed in formalin. For histologic analysis, tissues were embedded in paraffin, sectioned (7 µm), and stained with hematoxylin and eosin. Thyroids were scored quantitatively for G-EAT severity, using a scale of 1+ to 5+ according to previously established criteria [2
]. Thyroiditis (1+) is defined as an infiltrate of at least 125 cells in one or several foci; 2+ indicates 10–20 foci of cellular infiltration involving up to 25% of the gland; 3+ indicates that 25–50% of the gland is infiltrated; 4+ indicates that >50% of the gland is destroyed; 5+ indicates virtually complete destruction of the gland with few or no remaining follicles. Thyroid inflammatory lesions were also evaluated qualitatively. In general, thyroids with 1–2+ severity scores have infiltrates consisting mainly of lymphocytes with few neutrophils. The more severely destroyed thyroids (4–5+) had granulomatous changes with thyroid epithelial cell (TEC) proliferation, multinucleated giant cells, large numbers of histiocytes, numerous lymphocytes and neutrophils, microabscesses and necrosis, as well as fibrin deposition and variable degrees of fibrosis. The granulomatous inflammation at day 21 in thyroids, graded 4+ to 5+ characteristically, extended beyond the thyroid to involve the adjacent connective tissue and muscle. For evaluation of collagen deposition, some thyroid sections were stained using Masson’s trichrome [6
].
Immunoperoxidase staining
Terminal deoxynucleotide transferase-mediated deoxynucleotide triphosphate nick-end labeling (TUNEL; Apoptag kit, Intergen Co., Purchase, NY) assay was used to detect apoptosis [13
]. Staining of -SMA (clone 1A4, Sigma Chemical Co.), cytokeratin (clone PCK-26, Sigma Chemical Co.), Bcl-XL (H-62, Santa Cruz Biotechnology, Santa Cruz, CA), and Fas-associated death domain protein-like IL-1ß-converting enzyme-like inhibitory protein (FLIP; H-150, Santa Cruz Biotechnology) was performed using the immunoperoxidase method as described previously [4
, 5
]. Cellular proliferation was analyzed for proliferating cell nuclear antigen (PCNA; P10, Sigma Chemical Co.) or Ki-67 (Dako, Carpinteria, CA) on sections of formalin-fixed and paraffin-embedded thyroid tissues. Immunoperoxidase staining for PCNA was performed on deparaffined, rehydrated sections of 7 um thickness using a mouse anti-PCNA mAb (1/400) and the ABC Elite Vectastain kit (Vector Laboratories, Burlingame, CA). Only cells showing distinct nuclear staining were considered positive. Dual-staining of PCNA or TUNEL with cytokeratin or -SMA was used to detect apoptosis and proliferation in thyrocytes versus myofbs. Nonimmune mouse or goat Ig at an equivalent concentration was used as negative controls. These controls were always negative. All immunostaining was performed with tissue sections from three to four individual animals per group from at least three separate experiments. Results shown are representative of all animals tested, and representative areas of each slide are shown.
Confocal laser scanning double-immunofluorescence microscopy
To detect more specifically apoptosis and proliferation between myofbs and thyrocytes, dual-color immunofluorescence and confocal laser scanning microscopy were done. Prior to staining, tissue sections were pretreated by microwave irradiation for antigen retrieval [5
]. Myofbs were recognized using fluorescein isothiocyanate (FITC)-labeled mouse anti--SMA (clone 1A4, Sigma Chemical Co.), and thyroid follicular cells were detected by pan-cytokeratin staining using FITC-labeled PCK-26 (Sigma Chemical Co.). Apoptosis was detected using an in situ cell death kit (Roche, Nutley, NJ), and cell proliferation was detected by anti-Ki-67 (clone TEC-3, Dako). Slides were observed with a BioRad Radiance 2000 confocal system coupled to an Olympus IX70 inverted microscope.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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–/– and anti-TGF-ß-treated WT mice–/– mice by adoptive transfer of MTg-sensitized donor spleen cells activated in vitro by MTg and IL-12 [4
5
6
]. In WT and IFN-–/– recipients, thyroid lesions reached maximum severity (4–5+) 19–21 days after cell transfer [4
, 14
]. Collagen deposition was evident in WT and IFN-–/– thyroids 19 days after cell transfer. Thyroids became fibrotic and were still completely destroyed (5+ severity) at 35–50 days in WT mice, but thyroid lesions resolved almost completely with 0–1+ severity in IFN-–/– mice [4
]. TGF-ß1 is a key cytokine in the pathogenesis of fibrosis, and neutralization of TGF-ß can ameliorate fibrosis [8
]. Overexpression of TGF-ß resulted in marked thyroid fibrosis in WT mice, and this was significantly reduced by anti-TGF-ß1 [6
].
As myofbs participate actively in the development of fibrosis [8
9
10
11
12
], we first assessed the presence of myofbs in thyroids of mice with G-EAT. As shown in Figure 1A
and 1B
, thyroids of WT mice with severe (5+) G-EAT at day 21 had extensive infiltration by myofbs, which express -SMA. Myofbs persisted in WT thyroids at day 45 (Fig. 1C
and 1D)
when fibrosis was more extensive. In IFN-–/– thyroids, there was relatively less accumulation of myofbs at day 19 (Fig. 1E
and 1F)
, although G-EAT severity and inflammation were nearly as severe (Fig. 1E and 1F)
as in WT thyroids (Fig. 1A
and 1B)
. However, myofbs were not detected in resolving thyroids with a severity of 1+ at day 45 (Fig. 1G
and 1H)
. Collagen deposition was usually detectable in IFN-–/– thyroids at day 19 but not in thyroids in which inflammation was resolving (not shown). Compared with WT mice, the number of infiltrating myofbs was also relatively less at day 19 in thyroids of anti-TGF-ß-treated WT mice (Fig. 1I
and 1J)
, and there were few if any myofbs at day 45 (Fig. 1K
and 1L)
. Fibrosis was inhibited, and inflammation was beginning to resolve in mice given anti-TGF-ß.
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–/– thyroids–/– thyroids were infiltrating inflammatory cells at day 19 (Fig. 2C
and 2D)
. These results showed that there was early apoptosis of thyrocytes, which coincided with destruction of the thyroid and subsequent development of fibrosis in WT thyroids, and apoptosis of infiltrating cells was dominant in IFN-–/– thyroid lesions that would resolve by day 45.
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-SMA with FLIP or Bcl-XL for confocal analysis. However, the location of accumulated -SMA-positive myofbs at the periphery of thyroids (Fig. 1A)
was coincided with FLIP (Fig. 2E
and 2G)
or Bcl-XL (not shown), suggesting these apoptotic molecules were expressed by myofbs (Fig. 2E
2F
2G
2H
2I
2J)
. The results showed that myofbs in WT thyroids expressed FLIP (Fig. 2E
and 2F)
and Bcl-XL (Fig. 2I)
at the peak of G-EAT. Compared with WT thyroids, expression of FLIP (Fig. 2G
and 2H) and Bcl-XL (Fig. 2J)
by myofbs was significantly reduced in IFN-–/– thyroids. It is interesting that FLIP was not expressed on TEC in WT thyroids (Fig. 2E
, arrowheads) but was expressed by TEC in IFN-–/– thyroids (Fig. 2G , arrowheads) [4
]. Together, these data suggested that FLIP expression is differentially regulated in IFN-–/– versus WT thyroids during development of G-EAT. Bcl-XL functions as a dominant regulator of apoptotic cell death [16
17
18
], and FLIP is an important inhibitor in the initial upstream steps of Fas and tumor necrosis factor -mediated apoptosis [17
]. Thus, these antiapoptotic molecules may function to protect myofbs from apoptotic death.
Imbalance of apoptosis between thyrocytes and myofbs during development of thyroid fibrosis in G-EAT
The above results suggested that there may be an imbalance of apoptosis between myofbs and TEC, which could contribute to the different outcomes of inflammation in WT or IFN-–/– thyroids or thyroids of anti-TGF-ß-treated WT mice. To test this hypothesis, apoptosis/cytokeratin and apoptosis/-SMA dual-staining was performed to identify apoptotic thyrocytes or myofbs by confocal microscopy.
Thyrocytes were identified by cytokeratin (green color), and apoptosis was detected as red nuclear staining using an in situ cell death kit (Fig. 3
). Apoptosis was predominant in day 19 WT thyroids (Fig. 3A)
compared with IFN-–/– thyroids (Fig. 3B)
or thyroids of anti-TGF-ß-treated WT mice (Fig. 3C)
. Although there were few intact thyroid follicles in WT thyroids (Fig. 3A)
with severe (5+) inflammation (Fig. 1A and 1B)
, most intact thyroid follicles were apoptotic (Fig. 3A , Overlap). As IFN-–/– thyroids (Fig. 1E
and 1F) and thyroids from anti-TGF-ß-treated WT mice (Fig. 1I
and 1J)
had inflammation comparable with that of WT thyroids (Fig. 1A
and 1B)
with a severity of 4–5+ at day 19, thyrocytes in IFN-–/– or anti-TGF-ß-treated WT mice may be at risk for destruction by the inflammatory process. Although the nuclei of some thyrocytes were positive for apoptosis, suggesting some TEC were indeed destroyed by apoptosis in these mice, there was less apoptosis in thyrocytes of IFN-–/– (Fig. 3B)
or anti-TGF-ß-treated WT mice (Fig. 3C)
than in untreated WT mice (Fig. 3A)
. The decreased apoptosis of thyrocytes in anti-TGF-ß-treated WT mice (Fig. 3C) compared with untreated WT mice was consistent with results obtained by dual-staining of cytokeratin/TUNEL using an ABC peroxidase kit (Table 1
). Thus, extensive apoptotic destruction of thyrocytes occurred in WT but not in IFN-–/– thyroids or thyroids of anti-TGF-ß-treated WT mice.
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-SMA (myofbs, green staining of cytoplasm) and in situ cell death (red staining of nuclei) with confocal analysis were used to identify apoptotic myofbs. As shown in Figure 3D
, only a few infiltrating myofbs in WT thyroids were apoptotic. Compared with WT thyroids, more myofbs were apoptotic in thyroids of IFN-–/– (Fig. 3E)
and anti-TGF-ß-treated WT mice (Fig. 3F)
. Dual-staining of -SMA/TUNEL using an ABC peroxidase kit also showed more apoptosis of myofbs in thyroids of anti-TGF-ß-treated WT mice compared with untreated WT mice (Table 1)
. These results suggested that the accumulation of myofbs in WT thyroids at day 19 (Fig. 1A)
may result from resistance of myofbs to apoptosis, and expression of antiapoptotic molecules Bcl-XL and FLIP by myofbs (Fig. 2E
and 2F)
may contribute to their resistance to apoptosis.
Imbalance of proliferation between thyrocytes and myofbs during development of thyroid fibrosis
Development of fibrosis in WT mice could also result from proliferation of myofbs, which leads to the accumulation and persistence of myofbs in WT thyroids, and resolution of G-EAT may be a result of proliferation of TEC, contributing to the regeneration of TEC. As thyrocytes and myofbs have the ability to proliferate [12
, 19
], we next asked if there were differences in proliferation between these two types of cells during development of fibrosis.
Ki-67 is a nuclear protein, which is expressed during the cell cycle but not in resting cells [20
] and is an excellent marker for assessing cell proliferation. Dual-staining of Ki-67 with cytokeratin or -SMA was analyzed by confocal microscopy. Some WT thyrocytes showed proliferation with variable staining for Ki-67 during development of fibrosis (Fig. 4A
). However, the degree of thyrocyte proliferation was less than in IFN-–/– mice (Fig. 4A
and 4B)
. In contrast to WT mice, Ki-67 was predominant on thyrocytes in IFN-–/– mice (Fig. 4B)
, demonstrating that thyrocytes were actively proliferating. Ki-67 was also expressed predominantly by thyrocytes in anti-TGF-ß-treated WT mice (Table 1)
.
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–/– mice, few myofbs were Ki-67-positive (Fig. 4D)
, suggesting their ability to proliferate may be inhibited. Similarly, expression of Ki-67 on myofbs in thyroids of anti-TGF-ß-treated WT mice was less than in WT thyroids (Table 1)
. The fact that Ki-67 was strongly expressed by myofbs in WT thyroids suggests that proliferation of myofbs is another feature related to the progressive thyroid fibrosis in WT mice.
The results of immunohistochemical and confocal stainings are summarized in Table 1
. Together, these results indicate that the balance of the death and proliferation between myofbs and thyrocytes during the course of G-EAT may result in different outcomes of an autoimmune inflammatory response. Regulation of pro-/antiapoptotic molecules by IFN- or TGF-ß may play an important role in controlling the fate (apoptosis vs. proliferation) of infiltrating cells versus TEC in G-EAT thyroids.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Several observations support the hypothesis that an imbalance of apoptosis between thyrocytes and myofbs determines the outcome of G-EAT. At the peak of disease in WT mice, thyroids showed marked thyrocyte apoptosis, and most myofbs were not apoptotic (Fig. 3A
and 3D)
. Other studies have also emphasized the importance of apoptosis in fibrosis. For example, by detecting expression of bcl-2, BAX, Fas, and FasL in fibrotic tissues, it was suggested that induction of apoptotic molecules may enhance susceptibility of tissue cells to apoptosis [22
]. In the kidney, accelerated apoptosis of tissue cells was associated with areas of fibrosis and hypocellularity [23
, 24
]. Conversely, resistance of fibroblasts to apoptosis may result in failure to eliminate TGF-ß1 receptor overexpressing fibroblasts, leading to overproduction of ECM and fibrosis [25
26
27
]. It is interesting that in the present study, there were similar patterns of apoptosis between thyrocytes and myofbs in IFN-–/– and anti-TGF-ß-treated WT mice in which G-EAT resolved without fibrosis.
There was prominent apoptosis of activated myofbs during resolution of G-EAT in IFN-–/– and anti-TGF-ß-treated WT mice, and this correlated with decreased myofbs infiltrating the thyroids at days 35–45. Apoptosis, therefore, effectively removed the activated myofbs that overproduced ECM. Similar mechanisms exist to remove "professional" ECM-producing cells such as myofbs or myofb-like cells in other organs during wound healing and resolution of fibrosis [9
]. This study showed that during progressive fibrosis, there is proliferation and apoptosis of myofb, suggesting there is increased turnover of these cells, but proliferation predominates such that there is a net increase in myofb numbers. During resolution, apoptosis becomes the over-riding process with resulting net loss of myofbs in the thyroid.
Thyroid fibrosis may result not only from an imbalance of apoptosis of thyrocytes versus myofbs but also an imbalance of proliferation between these two types of cells. Dual-staining of PCNA or Ki-67 with cytokeratin or -smooth muscle actin was used to detect proliferation in thyrocytes versus myofbs. Only a few myofbs exhibited apoptosis, and they proliferated during development of fibrosis (Figs. 3D
and Fig. 4C
). In contrast, in IFN-–/– or anti-TGF-ß-treated WT mice, although some thyrocytes were apoptotic at days 14–21, many thyroid follicles were positive for PCNA or Ki-67, resulting in resolution of G-EAT. These results showed that there was less apoptotic death and excessive proliferation of myofbs in conjunction with a loss of thyrocytes by apoptosis and less proliferation of thyrocytes in WT thyroids. Together, these factors may facilitate development of fibrosis resulting from a disproportionate increase in the density of ECM. In contrast, in IFN-–/– or anti-TGF-ß-treated WT mice, disappearance of myofbs from G-EAT thyroids was a result of apoptotic death and less proliferation, and thyrocytes showed less apoptotic destruction and more proliferation, resulting in regeneration of follicles. Thus, there appears to be a biological conflict involving cell death and proliferation between myofbs and thyrocytes, which is important in determining the outcome of G-EAT to fibrosis or resolution. The similar findings in IFN-–/– and anti-TGF-ß-treated WT mice suggest that the net outcome of apoptosis and proliferation of myofbs and thyrocytes were responsible for reduction of fibrosis and eventual resolution of G-EAT inflammation in both cases.
The mechanisms that control the apoptotic death of myofbs and thyrocytes are not clear but may be related to the role of IFN- and TGF-ß1 on apoptosis and proliferation, directly or indirectly on different cell types. Strong expression of antiapoptotic molecules FLIP and Bcl-XL by myofbs (Fig. 2
2E
2F 2I
, and Table 1
) may make myofbs in WT thyroids resistant to apoptosis. The fact that FLIP expression was up-regulated in IFN-–/– thyrocytes (Fig. 2G)
[4
] suggests cytokines may play an important role in modulating the expression of apoptotic or antiapoptotic molecules. In wounds that heal without scarring, there was a notable lack of myofbs, but myofbs increased with time as tissue fibrosis progressed and was associated with expression of TGF-ß1 [10
, 28
]. In rheumatoid arthritis, synovial fibroblasts had decreased sensitivity to apoptosis, and TGF-ß1 may influence the sensitivity of these synovial fibroblasts to apoptosis [29
]. In vitro, many cytokines have been shown to affect susceptibility of cells to apoptosis [30
, 31
]. TGF-ß1 represents the initial triggering molecule for induction of fibrosis as well as apoptosis [8
, 32
33
34
]. Our observation of high expression of TGF-ß1 in areas of apoptotic thyrocytes and accumulated myofbs suggests a possible role of TGF-ß1 in affecting the apoptosis versus proliferation between thyrocytes and myofbs. Apoptosis may be pivotal for the pathogenesis of thyroiditis [35
], and TGF-ß1 may play a role in the control of thyroid growth by inducing apoptosis and arresting proliferation [36
]. Therefore, although TGF-ß1 inhibits proliferation of most cells, it may enhance production of fibroblasts and induce their activation to myofbs [32
, 37
, 38
], which are a major source of TGF-ß1 [5
]. Our results showed more proliferation but less apoptosis of myofbs and more apoptosis but less proliferation of thyrocytes in WT thyroids that developed fibrosis (Figs. 3A
and 4C)
. The opposite was true when mice were given anti-TGF-ß1. In IFN-–/– mice, active TGF-ß expression was also reduced compared with WT thyoids [4
]. These data suggest that TGF-ß1 may have a distinct role in survival of myofbs and thyrocytes, which is important for the outcome of G-EAT. How TGF-ß1 and/or IFN- differentially regulate apoptosis and proliferation of myofbs and thyrocytes is an important question that will require further studies.
The results presented here showed that disturbances in these homeostatic mechanisms can contribute to the development of fibrosis, giving myofbs a selective growth advantage because of accelerated rates of cell proliferation and decreased rates of cell death, and thyrocytes have accelerated rates of apoptosis and decreased rates of proliferation. When this mechanism is not operative, such as in IFN-–/– or anti-TGF-ß-treated WT mice, fibrosis is reduced, and inflammation eventually resolves. Therefore, an imbalance of cell death and proliferation between these two types of cells appears to control the outcome of autoimmune thyroid inflammation. These data also indicate that the fibrotic process is dynamic, fibrosis has the capacity for recovery, and restoration of the normal thyroid architecture is possible.
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ACKNOWLEDGEMENTS |
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Received September 19, 2004; revised October 15, 2004; accepted October 17, 2004.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-deficient mice develop severe granulomatous experimental autoimmune thyroiditis with eosinophil infiltration in thyroids J. Immunol. 160,5105-5112This article has been cited by other articles:
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