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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 666-669
Copyright © 1997 by The Endocrine Society

Experimental Studies

Detection of IL-12, IL-13, and IL-15 Messenger Ribonucleic Acid in the Thyroid of Patients with Autoimmune Thyroid Disease1

R. A. Ajjan, P. F. Watson and A. P. Weetman2

Department of Medicine, University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7AU, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
IL-12, IL-13, and IL-15 are important cytokines that have not been studied previously in human autoimmune thyroid diseases. By applying RT-PCR on RNA extracted from tissue samples, we have investigated in vivo gene expression of these cytokines in multinodular goiter (MNG), Graves’ disease (GD), and Hashimoto’s thyroiditis (HT). In addition, in vitro studies were carried out using the transformed human thyroid cell line, HT-ori3, and primary thyroid cell cultures derived from patients with GD. These cells were used either unstimulated or stimulated for 12 h with TSH, IL-1, or interferon-{gamma} (IFN-{gamma}). IL-12 p40 gene expression was identified in 2 of 10 MNG samples, 6 of 12 GD, and 3 of 4 HT. HT-ori3 and primary thyroid cell cultures were positive for IL-12 p40 messenger RNA (mRNA) expression in both unstimulated and stimulated cell cultures. IL-13 mRNA was expressed in 2 MNG, 9 GD, and 1 HT sample. Both HT-ori3 and primary thyroid cultures expressed IL-13 after TSH, IL-1, or IFN-{gamma} stimulation; unstimulated primary cultures of thyroid cells, however, did not express IL-13. IL-15 gene expression was detected in 8 MNG, 8 GD, and 4 HT samples. HT-ori3 and primary thyroid cell cultures, stimulated with TSH, IL-1, or IFN-{gamma}, showed expression of this cytokine. Unstimulated cells showed only a weak expression. Our results indicate that the cytokine patterns in the various diseases studied are heterogeneous; that thyroid cells can express IL-12, IL-13, and IL-15 mRNA in culture, particularly after TSH, IL-1, or IFN-{gamma} stimulation; and that IL-15 is expressed in most of the tissue samples studied.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CYTOKINES are likely to play an important role in autoimmune thyroid disease. These molecules, produced by both infiltrating inflammatory cells and thyroid follicular cells (TFC) (1, 2, 3, 4, 5), are essential for T and B cell growth and differentiation and may affect TFC directly, inducing expression of major histocompatibility complex class II molecules and adhesion molecules (6, 7, 8, 9, 10, 11). In addition, cytokines can alter the growth and function of TFC (12, 13, 14, 15).

IL-12, IL-13, and IL-15 are recently defined cytokines that have not been studied previously in autoimmune thyroid disease in man. IL-12 is a heterodimeric cytokine composed of two subunits, p35 and p40, and is produced primarily by activated monocytes (reviewed in Ref.16). Transcripts of p35 gene are constitutively expressed in most cells studied, whereas p40 messenger RNA (mRNA) is usually restricted to cells able to produce the heterodimeric IL-12 (17), and its expression is more tightly regulated than that of p35 (18, 19). IL-12 enhances the cytotoxic activities of natural killer (NK) and T cells and induces the production of several cytokines, especially interferon-{gamma} (IFN-{gamma}). This cytokine therefore is likely to be involved in the generation of the Th1 helper T cell subset, which mediates delayed type hypersensitivity responses (20).

IL-13 is mainly produced by Th2 cells, the T cell subset which provides help for humoral immune responses, although Th1 cells also can produce IL-13 in man. IL-13 shares many features with IL-4, including priming towards a Th2 response. However, its biological activities seem to be more restricted (reviewed in Ref.21). Finally, IL-15 has similar properties to IL-2, in that it stimulates the proliferation of both T and B cells (22, 23). In contrast to IL-2, IL-15 is not produced by T cells, although a large variety of tissues and cells can produce this cytokine (22).

In view of the potential importance of IL-12, IL-13, and IL-15 in immune responses in general, and autoimmunity in particular, we have analyzed IL-12, IL-13, and IL-15 gene expression by RT-PCR in thyroid tissue samples obtained from patients with nontoxic multinodular goiter (MNG), Graves’ disease (GD), and Hashimoto’s thyroiditis (HT). This was complemented by in vitro studies carried out on primary TFC cultures and on the immortalized human thyroid cell line, HT-ori3, to determine whether TFC are a possible source of these cytokines.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patient samples

Tissue samples were processed, as described below, to obtain primary TFC cultures or immediately snap frozen in liquid nitrogen. The diagnosis was confirmed in all the patients by histological examination. All HT patients had high-antibody titers against thyroid peroxidase (anti-TPO), whereas 7 of 10 GD patients had raised anti-TPO titers, with data unavailable in another 2. All patients with HT and GD had been treated with T4 and carbimazole, respectively, before surgery. Local ethical committee approval was obtained, and all tissue samples were taken after informed consent.

Thyroid cell culture

The HT-ori3 cell line was established by transfection of normal thyroid cells with a plasmid-borne origin-defective SV40 genome as previously described (24). This cell line expresses features of thyroid epithelial function, including iodide trapping and thyroglobulin production. Primary TFC cultures were prepared from GD thyroidectomy specimens using methods described elsewhere (25). Both HT-ori3 and primary cell cultures were grown to confluence in 25-cm2 flasks and treated with IL-1, bovine TSH, or recombinant IFN-{gamma} as previously described (3). RNA was extracted from cell cultures after 12 h of stimulation.

RNA extraction and complementary DNA (cDNA) synthesis

RNA was extracted from thyroid cell culture and whole tissue (3-mm3 pieces) by using TRIzol (Gibco, Paisley, UK) according to the manufacturer’s protocol. Moloney murine leukemia virus RT was used to synthesize cDNA as previously described (3).

PCR amplification

PCR was performed in 50 µL amplification reaction, which contained: 5 µL of 10 x concentrated buffer (15 mmol/L MgCl2, 100 mmol/L Tris HCl pH 8.3, 0.1% gelatin, 500 mmol/L KCl, 1% Tween 20, 1% Nonidet NP40; all from Sigma, Poole, Dorset, UK), 2.5 units of Taq DNA polymerase (Promega, Southampton, UK), 0.1 mmol/L of each deoxyribonucleotide triphosphate, 1.5 µL cDNA, and 41 µL autoclaved deionized water.

Amplifications were carried out using cycles of 94 C for 1 min, 55 C for 1 min, and 72 C for 1 min. ß-actin was used as a control for the integrity of cDNA in the samples, and its amplification was performed using 27 cycles. Thirty-five cycles were used to amplify IL-13 cDNA and 39 cycles for the detection of IL-12 and IL-15.

To provide a positive control, normal peripheral blood mononuclear cells (PBMC) were stimulated with phytohemagglutinin M (PHA; Gibco; 1 µg/mL) for 24 h. Adherent PBMC were stimulated for 4 h with lipopolysaccharide (LPS) (10 µg/mL; Sigma). RNA was extracted from these two preparations, pooled together, and used to prepare cDNA as described above. The oligonucleotide primers and probes were designed according to previously published sequences of IL-12 (26), IL-13 (27), and IL-15 (22). The primer sequences were as follows: IL-12 p40: sense 5'-TACTCCTTGTTGTCCCCTCTG-3', antisense 5'-GTGGCCATATGGGAACTGAAG-3'; IL-13: sense 5'-GAAGACCCAGAGGATGCT-3', antisense 5'-CCGCCTACCCAAGACATT-3'; IL-15: sense 5'-CAAGATCGTATTGTATTGTAGGA-3', antisense 5'-ACATTTGGACAATATGTACAAAA-3'.

The primer sequences for ß-actin have been described previously (3).

Control reactions without cDNA were carried out in parallel and were consistently negative.

Oligonucleotide hybridization

Product identification was confirmed by hybridization using internal oligonucleotide probes as previously described (3). Probe sequences were as follows: IL-12 probe: 5'-CAGTACTAGTTTGACATTCAG-3'; IL-13 probe: 5'-CGCACAAGGTCTCAGCTG-3'; IL-15 probe: 5'-ACCGTGGCTTTGAGTAAT-3'.

The probe for ß-actin has been described previously (3).

Statistics

Results were compared by 2 x 2 contingency tables and the {chi}2 test (two-tailed).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Whole tissue

Ten MNG, 12 GD, and 4 HT tissue samples were analyzed for IL-12, IL-13, and IL-15 gene expression by RT-PCR. Representative results are illustrated in Fig. 1Go, where lanes 1–5 represent MNG, lanes 6–11, GD, and lanes 12–15, HT tissue samples. C+ represents the positive control obtained from PHA- and LPS-stimulated PBMC.



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  		Figure 1. Detection of IL-12, IL-13, and IL-15 gene expression in thyroid tissue samples using RT-PCR. Lanes 1–5, MNG; lanes 6–11, GD; and lanes 12–15, HT tissue samples. C+, positive PBMC control.

 
IL-12 p40 mRNA was detected in 2 of the MNG and 6 of the GD ({chi}2 = 2.12, P > 0.05 compared with MNG) and in 3 of the HT samples. Only 2 MNG and 1 HT samples expressed IL-13, whereas 8 GD samples showed bands for IL-13 ({chi}2 = 4.79, P < 0.03 compared with MNG). Eight of 10 MNG samples expressed IL-15; 9 GD samples showed also its expression ({chi}2 = 0.48, P > 0.05 compared with MNG). IL-15 was detected in all HT samples.

TFC and HT-ori3 cultures

The results of experiments to detect IL-12, IL-13, and IL-15 mRNA in cultured thyroid cells by RT-PCR are shown in Fig. 2Go. Lanes 1–4 represent cultured HT-ori3 cells, whereas lanes 5–8 are primary TFC cultures from a patient with GD. These cells were used either unstimulated (lanes 1 and 5) or stimulated with IL-1 (lanes 2 and 6), TSH (lanes 3 and 7), or IFN-{gamma} (lanes 4 and 8). C+ represents the positive control obtained from PHA- and LPS-stimulated PBMC. Using methods previously described (3), cDNA samples from both unstimulated and stimulated cells were equilibrated on the basis of the yield of ß-actin-specific PCR product, enabling approximate semiquantitation of the cytokines studied.



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  		Figure 2. Detection of IL-12, IL-13, and IL-15 gene expression in HT-ori3 (lanes 1–4) and primary TFC (lanes 5–8) cultures. Cells were used either unstimulated (lanes 1 and 5) or stimulated with IL-1 (lanes 2 and 6), TSH (lanes 3 and 7), or IFN-{gamma} (lanes 4 and 8). C+, positive PBMC control.

 
Unstimulated HT-ori3 cells (lane 1) expressed all three cytokines, whereas unstimulated primary TFC cultures (lane 5) expressed IL-12 and IL-15 only. After stimulation of either HT-ori3 cells or primary TFC cultures with TSH, IL-1, or IFN-{gamma}, there was an enhanced expression of IL-13 and IL-15, with IL-13 becoming detectable in the primary thyrocyte cultures. This experiment was repeated on two further occasions using TFC from separate GD patients, as well as replicate HT-ori3 cells, with similar results.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
RT-PCR is a sensitive technique for mRNA detection, but a drawback of this method is that mRNA expression does not necessarily correlate with protein secretion. In addition, the sensitivity of RT-PCR is a potential problem because the pathological role of signals detected can be questioned. Nonetheless, this technique has been valuable in detecting cytokine gene expression in autoimmune thyroid diseases, allowing small amounts of tissue to be analyzed (28, 29, 30).

IL-12 induces IFN-{gamma} production and is thought to play a critical role in the development of Th1 immune response (20). A recent study of BioBreeding (BB) autoimmune-thyroiditis-prone rats has shown that IL-12 p40 gene expression increases in the thyroid gland with the progression of the thyroiditis, implicating IL-12 in the perpetuation, if not the initiation, of the disease (31). In our study, 3 of 4 HT thyroid samples and 6 of 12 GD samples expressed IL-12 p40. Although IL-12 p40 was constitutively expressed in thyroid cultures, suggesting a contribution by TFC to IL-12 expression, it was detected in only 2 of the MNG tissue samples. This could be caused by unknown inhibitory factors operating to suppress IL-12 expression in vivo, or it could be simply caused by low levels of expression in this mixed cellular population.

IL-13 suppresses the production of proinflammatory cytokines and facilitates a Th2 response resulting in antibody synthesis (21). IL-4 is a key cytokine product of Th2 cells for this response. Previous studies on tissue IL-4 mRNA expression in GD have given conflicting results, in that IL-4 was either not expressed or found in a minority or detected in all of the samples analyzed (28, 29, 32). A recent study using quantitative RT-PCR has demonstrated a correlation between tissue IL-4 mRNA levels and serum levels of anti-TPO in patients with GD (33). The majority of our GD tissue specimens expressed IL-13, and all but one of the samples from patients with high anti-TPO titers showed IL-13 expression, suggesting a role for this cytokine in intrathyroidal autoantibody synthesis. However, one sample from a patient with undetectable anti-TPO also expressed IL-13; pretreatment with antithyroid drugs may have influenced antibody levels in these patients. Although anti-TPO antibody was detected in all HT patients, only one tissue sample expressed IL-13, but three of these samples, including the sample expressing IL-13, showed IL-4 expression (data not shown). IL-13 was either not detected or expressed as a faint band in unstimulated primary or HT-ori3 cell cultures, respectively. However, the results after TSH, IL-1, or IFN-{gamma} stimulation indicate that TFC could be a source of IL-13 in pathological settings.

IL-15 induces T and B cell proliferation (22, 23). This cytokine is expressed by a wide range of human tissues and cell lines, including skeletal muscle, placenta, and epithelial cell cultures (22). In keeping with this, IL-15 mRNA was detected in the majority of thyroid tissue samples from patients with MNG, GD, and HT. Furthermore, unstimulated primary TFC and HT-ori3 cultures expressed IL-15, and the expression was increased after stimulation of these cells with TSH, IL-1, or IFN-{gamma}, suggesting that TFC are a source of IL-15 in the thyroid. IL-15 is known to have noninflammatory actions because it can be detected in normal muscle tissue, where it is thought to have an anabolic activity (34). Although we have found a significant difference in IL-13 gene expression between the GD and the MNG, differences in IL-12 or IL-15 mRNA expression did not reach statistical significance. This could be caused by the variable contribution of TFC to expression of IL-12 and IL-15 by thyrocytes in both disorders, discussed above. Another possibility is the involvement of autoimmunity in the pathogenesis of MNG (35), making normal thyroid tissue the ideal control, but unfortunately, we have been unable to obtain truly normal thyroid. The HT group was not included in the statistical analysis because of the limited number of samples analyzed.

In summary, this study demonstrates the ability of TFC to express IL-12, IL-13, and IL-15 mRNA in culture, particularly after stimulation with TSH, IL-1, and IFN-{gamma}. IL-15 was detected in most of the thyroid tissue specimens studied. IL-12 and IL-13 were detected with varying frequencies in GD and HT tissue samples, whereas only a minority of MNG samples expressed these two cytokines. These results suggest that intrathyroidal production of IL-12, IL-13, and IL-15 are involved in the pathogenesis of autoimmune thyroid diseases.


   Acknowledgments
 
We are grateful to our surgical colleagues, Mr. B. Harrison and Mr. W. E. G. Thomas, for the provision of thyroid specimens. We would also like to thank Mrs. R. Davies and Mr. R. Metcalfe for excellent technical help.


   Footnotes
 
1 This work was supported by the Wellcome Trust. Back

2 To whom correspondence and requests for reprints should be addressed. Back

Received June 19, 1996.

Revised August 29, 1996.

Accepted October 7, 1996.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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