Review 597

IP-10 in Autoimmune Thyroiditis

Affiliations

Key words ▶ thyroid autoimmunity ● ▶ CXCL10 ● ▶ CXCR3 ● ▶ thyroid autoantibodies ●

I. Ruffilli1, S. M. Ferrari1, M. Colaci2, C. Ferri2, P. Fallahi1, A. Antonelli1 1 2

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Department of Medical, Surgical, Maternal, Pediatric and Adult Sciences, University of Modena and Reggio Emilia, Modena, Italy

Abstract



The interferon-γ-inducible protein 10 (IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. IP-10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3). IP-10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, Graves’ disease and ophthalmopathy), or systemic (such as systemic lupus erythematosus, mixed cryoglobulinemia, Sjogren syndrome, or systemic sclerosis). The secretion of IP-10 by (CD)4 + , CD8 + , and natural killer is dependent on IFN-γ. Under the influence of IFN-γ, IP-10 is secreted by thyrocytes.

Introduction received 03.04.2014 accepted 27.05.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1382053 Published online: June 30, 2014 Horm Metab Res 2014; 46: 597–602 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence A. Antonelli, MD Department of Clinical and Experimental Medicine University of Pisa Via Savi 10 56126 Pisa Italy Tel.: + 39/050/992 318 Fax: + 39/050/553 235 alessandro.antonelli@med. unipi.it



Chemokines are small glycoproteins (weighing 8–10 kDa) that are active for a wide variety of cell types, and their target cells express appropriate G protein receptors [1]. They are classified into 4 subfamilies including C, CC, CXC, and CX3C chemokines, based on the conserved cysteine motifs in their biochemical structure [1]. The interferon (IFN)-γ-inducible protein 10 (CXCL10, also called IP-10) was initially identified as a chemokine that is induced by IFN-γ and secreted by various cell types, such as neutrophils [2], endothelial cells [3], keratinocytes [4], fibroblasts [5], dendritic cells [6], astrocytes [7], and hepatocytes [8]. IP-10 binds to chemokine (C-X-C motif) receptor (CXCR3) and regulates immune responses by activation and recruitment of leukocytes, including T cells, monocytes, and natural killer cells [9, 10]. CXCR3 is expressed by not only by immune cells but also by resident cells such as endothelial cells and mesangial cells. Recently, accumulating reports have shown that the serum and/or the tissue expressions of IP-10 are increased in various autoimmune diseases [8].

Determination of high level of IP-10 in peripheral fluids is therefore a marker of a T helper 1 orientated immune response. High levels of circulating IP-10, have been shown in patients with autoimmune thyroiditis (AT). Among patients with AT, IP-10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, which is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons, it has been postulated that IP-10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether IP-10 is a novel therapeutic target in AT.

IP-10 and CXCR3 play fundamental parts in leukocyte homing to inflamed tissues and in the perpetuation of inflammation and importantly contribute to the process of tissue damage. In this article, we will focus on the role of IP-10 as a marker of autoimmune thyroiditis (AT). We have searched published studies in PubMed databases covering the period from 1995 to January 2014. Literature search was carried out using the combination of terms “IP-10”, or “CXCL10”, or “CXCR3”, with: “thyroiditis”, “autoimmune thyroiditis”, “thyroid autoantibodies”, “hypothyroidism”, “thyroid diseases”, “thyroid disorders”, and “thyroid dysfunction”.

IP-10 in Autoimmunity



IP-10 secretion is dependent on IFN-γ, which itself is mediated by the interleukin (IL)-12 cytokine family [11]. Under the influence of cytokines, IP-10 is secreted by several cell types, including T lymphocytes, monocytes, splenocytes, fibroblasts, keratinocytes, thyrocytes, preadipocytes, etc. Determination of high level of

Ruffilli I et al. IP-10 in Thyroiditis … Horm Metab Res 2014; 46: 597–602

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Authors

IP-10 in peripheral liquids is therefore a marker of host immune response, especially T helper (Th)1 orientated T-cells. Recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor (TNF)-α production, which in turn stimulates IP-10 secretion from a variety of the above-mentioned cells, therefore creating an amplification feedback loop [12]. Circulating IP-10 levels increase with age [13]. Furthermore, recent reports have shown that the serum and/or the tissue expressions of IP-10 are increased in organ specific autoimmune diseases, such as Graves’ disease, or Graves’ ophthalmopathy [14, 15], type 1 diabetes [16–21], or systemic rheumatological disorders like rheumatoid arthritis [22], systemic lupus erythematosus [23], systemic sclerosis [24, 25], psoriatic arthritits [26–28], sarcoidosis [29, 30], “hepatitis C virus chronic infection” (HCV)-related cryoglobulinemia [31, 32], and other autoimmune HCV related disorders [33, 34].

Autoimmune Thyroiditis (AT)



AT, also known as chronic lymphocytic or Hashimoto’s thyroiditis is characterized by infiltration of the thyroid gland by inflammatory cells and production of autoantibodies to thyroid-specific antigens such as thyroglobulin and thyroperoxidase [35]. It is accompanied by hypothyroidism due to destruction and eventual fibrous replacement of the follicle cells. AT results from a deregulation of the immune system leading to an immune attack on the thyroid gland. AT is clearly multifactorial in etiology with genetic and environmental factors contributions [36]. Combined data from etiological modeling statistics and from twin studies showed that about 80 % of AT susceptibility is due to genetic factors. Among susceptibility genes, HLA-DRβ1-Arg74 confers the strongest risk. Recent genome-wide analyses have revealed new putative candidate genes [37]. The remaining 20 % of environmental triggers, include stress, smoking, dietary iodine, selenium intake and infection [38]. Epigenetic modulation is emerging as a major mechanism by which environmental factors interact with autoimmune thyroid diseases susceptibility genes [39]. Overall, AT affects up to 5 % of the general population, with a female/male ratio of 4:1. The incidence of AT has markedly risen in recent years. In Italy an increased incidence of AT has been reported both in the endocrinology clinics setting such as in thyroid diagnostic cytology setting. The cause of this rising incidence is unexplained [40–42]. Many studies have underlined the importance of a Th1 immune response in the immunopathogenesis of AT [43, 44]. However more recently other studies indicate that there is an increased differentiation of Th17 lymphocytes and an enhanced synthesis of Th17 cytokines in AT [45, 46].

▶ Table 1) IP-10 in Autoimmune Thyroiditis (●



By using immunohystochemistry, a statistically significant increase of IP-10 in thyroid tissue specimens obtained from subjects affected by Hashimoto’s thyroiditis was found [47]. Within thyroid tissue from Hashimoto’s patients, there was evidence for the expression of IP-10 chemokines by thyroid follicular cells, suggesting a role for local chemokine synthesis by the

glandular epithelial cells in the recruitment of inflammatory cells into the gland in autoimmunity [48]. To determine the chemokines profile expressed in the thyroid gland upon chronic exposure to IFN-γ, Kimura et al. analyzed C57BL6 transgenic mice that aberrantly express IFN-γ under control of the thyroglobulin promoter. They found that transgenics showed increased expression of IP-10. This chemokine profile was associated with moderate mononuclear cell infiltration of the thyroid stroma [49]. In humans, serum IP-10 concentrations were measured in 223 consecutive patients with newly diagnosed AT, 97 euthyroid controls, and 29 patients with nontoxic multinodular goiter to relate this parameter to the clinical phenotype. Serum IP-10 level was significantly higher in AT patients (157 ± 139 pg/ml) than in controls (79 ± 38 pg/ml) or patients with multinodular goiter (90 ± 32 pg/ml; p < 0.0001). Among patients with AT, IP-10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern and hypothyroidism [50]. These data suggest the involvement of Th1 immune response in the early phase of AT, and exclude the involvement of the Th2 chemokine (C-C motif) ligand 2 (CCL2) chemokine [51]. Also other studies in patients with AT, and other immune mediated disorders, such as systemic sclerosis, mixed cryoglobulinemia, HCV, and psoriatic arthritis, confirmed a strong association among high levels of IP-10 and thyroid autoimmunity, independent from the other associated immune mediated disorder [25, 27, 32, 52–55]. These findings suggest that a common immunopathogenetic pattern is present in patients with AT and the above-mentioned immunomediated disorders, that involves the Th1 immunity and the IP-10 chemokine [12, 56]. It has been postulated that IP-10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism [57]. These findings are in line with experimental evidence demonstrating that a Th1 enriched microenvironment leads to a more severe course of thyroiditis resulting in thyrocyte apoptosis and hypothyroidism [49]. Other studies have shown a strong correlation between circulating monokine induced by IFN-γ (MIG) or IFN-inducible T-cell α chemoattractant (I-TAC) and

Table 1 CXCL10 in tissue and circulation in patients with autoimmune thyroiditis. Ref.

Year

No.

CXCL10

Patients

Results

Thyroiditis Thyroiditis

Increased Increased

in tissue

47 48

2001 2003

50 51 25 27 52

2004 2005 2008 2008 2008

53 54 55 57 58 59 60

2008 2009 2010 2006 2011 2012 2012

Thyroid Thyroid

CXCL10 in blood Thyroiditis Thyroiditis Thyroiditis + systemic sclerosis Thyroiditis + psoriatic arthritis Thyroiditis + hepatitis C HCV-associated cryoglobulinemia Thyroiditis + HCV-cryoglobulinemia Thyroiditis + HCV Thyroiditis + HCV-cryoglobulinemia Thyroiditis + hypothyroidism Thyroiditis Thyroiditis + HCV-cryoglobulinemia Thyroiditis

Increased = increased vs. appropriate control

Ruffilli I et al. IP-10 in Thyroiditis … Horm Metab Res 2014; 46: 597–602

Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased Increased

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598 Review

Review 599



The possible association between AT and papillary thyroid carcinoma (PTC) is a still debated issue [64]. A systematic literature review of original studies that investigated the correlation between AT and PTC reported conflicting results; some suggest that these 2 are positively correlated, whereas other studies report no relationship. Population-based fine-needle aspiration biopsy studies report no linkage, whereas many of the studies on thyroidectomy specimens report a positive relationship. In addition, there are many studies in the literature that propose a genetic link between Hashimoto’s thyroiditis and PTC involving the PI3K/Akt pathway and RET/PTC gene rearrangements [65]. However, recent findings have shown that the frequency of PTC is significantly higher in nodular-AT than in nodular goiter and is associated with increased levels of serum thyroid stimulating hormone [66]. In addition, other studies have previously shown a possible association between PTC and AT [67, 68]. The association of PTC and AT is clinically relevant since about 15–30 % of these patients may show an aggressive disease, for example with lung metastases, which is difficult to treat [69– 72]. Recently in PTC, rearrangements of the RET receptor (RET/ PTC) and activating mutations in the BRAF or RAS oncogenes activate a common transcriptional program in thyroid cells that includes upregulation of the IP-10 chemokine, which in turn stimulates proliferation and invasion [73]. More recently, we have shown that a more than 10 times higher IP-10 secretion has been induced by IFN-γ + TNF-α in PTCs with respect to normal

IFN-γ + TNF-α

oid f

ollicl

es

(+)

PPAR-α PPAR-γ CORTICOSTEROIDS

CXCL10

(–)

(+) IFN-γ + TNF-α

Lymphocytes recruitment

Fig. 1 Thyroid follicular cells, under the influence of cytokines (such as IFN-γ and TNF-α), can modulate the autoimmune response through the production of CXCL10. This chemokine can induce the migration into the thyroid of Th1 lymphocytes, which in turn, secrete more IFN-γ and TNF-α, further stimulating the chemokine production by the target cells, thus perpetuating the autoimmune cascade. PPAR-γ and PPAR-α agonists and corticosteroids play an inhibitory role in this process.

thyroid follicular cells [74]. In addition, other studies have shown an important role of IP-10 in PTC [75].

Targeting CXCR3 and IP-10 in Thyroid Autoimmunity



There are several models for interfering with the chemokine system, which are represented by small antagonist molecules, modified chemokines, neutralizing monoclonal antibodies, binding proteins [76]. Many studies have evaluated the possibility of modulating the cytokine-induced chemokine secretion, using mainly primary human cell cultures [8]. Peroxisome proliferator-activated receptor gamma (PPAR)-γ has recently been shown to be involved in the modulation of inflammatory responses. PPAR-γ activity may be involved in the regulation of IFN-γ-induced chemokine expression in human autoimmunity, and PPAR-γ activators might attenuate the recruitment of activated T cells at sites of Th1-mediated inflammation [77–79]. Treatment of thyrocytes, orbital fibroblasts, and preadipocytes cell types with the PPAR-γ agonist rosiglitazone, dose-dependently (0.1–10 μM) suppressed IFN-γ plus TNF-α-induced IP-10 release, suggesting an inhibitory role of PPAR-γ agonists in the modulation of CXCR3 chemokines [15, 62]. Future studies will be needed to verify if new targeted PPAR-γ activators may be able to exert the anti-inflammatory effects without the risk of expanding retrobulbar fat mass [80]. Ligands for PPAR-α have therapeutic activity in several rodent models of inflammatory and autoimmune diseases [81, 82], suggesting that they might have similar activity in human disease as well. About chemokines, it has been shown recently that fenofibrate represses IL-17 and IFN-γ expression and improves colitis in IL-10 deficient mice, by inhibiting the expression of the gene encoding IP-10, and by repressing IP-10 gene promoter activity in TNF-α-treated HT-29 cells [83]. Recent data show that PPAR-α activators inhibit the secretion of IP-10 and CCL2 in thyrocytes, suggesting that PPAR-α may be involved in the modulation of the immune response in the thyRuffilli I et al. IP-10 in Thyroiditis … Horm Metab Res 2014; 46: 597–602

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IP-10 in Thyroid Cancer in the Presence of Thyroid Autoimmunity

Th1 Lymphocytes

Thyr

IP-10 in AT patients. These results underline the importance of a Th1 immune attack in the initiation of AT [58–60]. The interaction between IP-10 binding chemokines and CXCR3 plays an important role in the Th1 immune response, which is responsible for the so-called organ specific autoimmune diseases. Indeed IP-10 is a powerful recruiter of Th1 cells expressing CXCR3 into target tissues. Furthermore, the role of CXCR3 binding chemokines in amplifying the Th immune response goes behind just the recruitment of the Th1 cells in inflamed tissues. In fact, IP-10 also acts as co-stimulator of IFN-γ production by CD4 + T-cells, therefore inducing a unique cytokine/chemokine positive feedback loop that amplifies the ongoing Th1 immune response. The final effect is the enhancement of inflammatory reactions characterized by the production of IFN-γ [61]. In primary cultures of normal human thyrocytes, IP-10 production was absent under basal conditions. Dose-dependent secretion of IP-10 was induced by IFN-γ, while TNF-α alone had no effect. The stimulation with IFN-γ in combination with TNF-α induced a synergistic release of IP-10 with respect to IFN-γ alone, which increased from about 220 pg/ml to about 1 600 pg/ ml in the thyrocytes supernatant [62]. Other studies have subsequently confirmed the above-mentioned results [63]. ▶ Fig. 1), based on the above-mentioned data, it In conclusion (● is evident that thyroid follicular cells, under the influence of cytokines (such as IFN-γ and TNF-α), can modulate the autoimmune response through the production of the IP-10 chemokine. This chemokine can induce the migration of Th1 lymphocytes into the thyroid, which in turn, secrete more IFN-γ and TNF-α, stimulating the chemokine production by the target cells, thus initiating and perpetuating the autoimmune cascade [15].

roid [84]. PPAR ligands repress transcriptional activation by nuclear factor-κB (NF-κB) via a mechanism known as liganddependent transrepression [85, 86]; thus, NF-κB is a likely target for repression of IP-10 transcription by PPAR-α agonists.

Conclusion



IP-10 and its receptor, CXCR3, appear to contribute to the pathogenesis of AT. Under the influence of IFN-γ, IP-10 is secreted by thyrocytes. In tissue, recruited Th1 lymphocytes may be responsible for enhanced IFN-γ, which in turn stimulates IP-10 secretion from thyrocytes creating an amplification feedback loop, and perpetuating the autoimmune process. Determination of high level of IP-10 in peripheral liquids is therefore a marker of Th1 orientated immune response. High levels of circulating IP-10 have been shown in patients with AT. Among patients with AT, IP-10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, which is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons, it has been postulated that IP-10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether IP-10 is a novel therapeutic target in AT.

Conflict of Interest



The authors declare that they have no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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IP-10 in autoimmune thyroiditis.

The interferon-γ-inducible protein 10 (IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. IP-10 exerts its function...
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