TGF-β Physiology as a Novel Therapeutic Target Regarding Autoimmune Thyroid Diseases: Where Do We Stand and What to Expect

Kardalas, Efstratios; Maraka, Spyridoula; Papagianni, Maria; Paltoglou, George; Siristatidis, Charalambos; Mastorakos, George

doi:10.3390/medicina57060621

Cited by 12 publications

(10 citation statements)

References 69 publications

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“…TGF-β plays a pivotal role in normal human immune response and is involved in the pathophysiological spectrum of thyroid autoimmunity [ 5 , 13 , 17 , 43 ]. Based on the clear interplay between TGF-β, EMT, and primary ciliogenesis [ 30 , 31 , 33 , 40 , 41 ], we studied EMT markers in AITD and found that thyroid follicular cells can acquire mesenchymal markers and still preserve their epithelial phenotype.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Epithelial–Mesenchymal Transition Markers in Autoimmune Thyroid Diseases

Sacristán-Gómez

Serrano-Somavilla

Castro-Espadas

et al. 2023

IJMS

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A state of chronic inflammation is common in organs affected by autoimmune disorders, such as autoimmune thyroid diseases (AITD). Epithelial cells, such as thyroid follicular cells (TFCs), can experience a total or partial transition to a mesenchymal phenotype under these conditions. One of the major cytokines involved in this phenomenon is transforming growth factor beta (TGF-β), which, at the initial stages of autoimmune disorders, plays an immunosuppressive role. However, at chronic stages, TGF- β contributes to fibrosis and/or transition to mesenchymal phenotypes. The importance of primary cilia (PC) has grown in recent decades as they have been shown to play a key role in cell signaling and maintaining cell structure and function as mechanoreceptors. Deficiencies of PC can trigger epithelial–mesenchymal transition (EMT) and exacerbate autoimmune diseases. A set of EMT markers (E-cadherin, vimentin, α-SMA, and fibronectin) were evaluated in thyroid tissues from AITD patients and controls through RT-qPCR, immunohistochemistry (IHC), and western blot (WB). We established an in vitro TGF-β–stimulation assay in a human thyroid cell line to assess EMT and PC disruption. EMT markers were evaluated in this model using RT-qPCR and WB, and PC was evaluated with a time-course immunofluorescence assay. We found an increased expression of the mesenchymal markers α-SMA and fibronectin in TFCs in the thyroid glands of AITD patients. Furthermore, E-cadherin expression was maintained in these patients compared to the controls. The TGF-β-stimulation assay showed an increase in EMT markers, including vimentin, α-SMA, and fibronectin in thyroid cells, as well as a disruption of PC. The TFCs from the AITD patients experienced a partial transition to a mesenchymal phenotype, preserving epithelial characteristics associated with a disruption in PC, which might contribute to AITD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Epithelial–Mesenchymal Transition Markers in Autoimmune Thyroid Diseases

Sacristán-Gómez

Serrano-Somavilla

Castro-Espadas

et al. 2023

IJMS

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“…Fibroblast between the second and fifth passages were used for analysis. [20][21][22][23] For adipogenesis, cells were cultured in serum-free DMEM supplemented with T3, insulin (Boehringer-Mannheim, Mannheim, Germany), carbaprostaglandin (cPGI2; Calbiochem, La Jolla, CA, U.S.A.), and dexamethasone. A peroxisome proliferator-activated receptor gamma agonist, rosiglitazone (10 μM; Cayman, Ann Arbor, MI, U.S.A.), was also added from day 1 of differentiation for heightened stimulation of adipogenesis.…”

Section: Methodsmentioning

confidence: 99%

The Effect of Rho Kinase Inhibitors on In Vitro Human Orbital Preadipocytes

Yoo,

Horacek,

Chae

et al. 2023

Ophthalmic Plastic &Amp; Reconstructive Surgery

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Purpose: To identify the effects of Rho Kinase (ROCK) inhibitor medications on human orbital adipogenesis, fibroblast proliferation, and fibrosis. Methods: Orbital adipose tissue was obtained from patients with Graves’ ophthalmopathy (GO) as well as controls (non-GO or normal) after informed consent was done. These tissue samples were cultured and adipogenesis was initiated. Levels of Rho Kinase as well as cellular mediators of orbital inflammation and fibrosis. The same cultures and measurements were then repeated with the use of a ROCK inhibitor (KD025-ROCK2) to assess for changes in adipogenesis as well as markers associated with inflammation and fibrosis. Results: Rho Kinase levels in GO tissue were more highly expressed than in controls. These levels were suppressed with the use of the ROCK inhibitor KD025. There was a dose-dependent reduction in differentiation of orbital adipocytes with the use of KD025. KD025 reduced the levels of fibrosis-related gene expression. Finally, there was a significant reduction of transforming growth factor beta mediated phosphorylation signaling pathways in the KD025-treated GO tissue. Conclusion: This study shows that the ROCK inhibitor, KD025, helps to reduce the expression of ROCK in GO tissue along with reducing orbital adipocyte differentiation as well as cell mediators involved in fibrosis that occurs in GO.

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“…ЭОП -аутоиммунное заболевание, осложняющее течение БГ. Глюкокортикоидная терапия является методом выбора лечения ЭОП, благода-ря ее противовоспалительному и иммуносупрессивному действию [10,18,22,24]. Частота положительного ответа на лечение наблюдается не у всех пациентов.…”

Section: заключениеunclassified

Transforming growth factor β1 (TGF-β1) in patients with endocrine ophthalmopathy and Graves’ disease: A predictor of treatment efficiency

Sviridenko¹,

Bessmertnaya²,

Беловалова³

et al. 2022

Med. immunol.

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Current therapeutic approaches to the treatment of endocrine ophthalmopathy (EOP) are based on nonspecific immunosuppression with glucocorticosteroids (GCs) and radiation therapy of the eye orbits. However, some patients exhibit resistance to the treatment. In a previous study, we have detected high levels of soluble cytokine receptors: sTNFα-R1, sTNFα-R2, sIL-2R, and the TGF-β1 cytokine in euthyroid patients with long-lasting non-treated EOP and Graves’ disease (GD). TGF-β1 level was significantly higher in the patients with EOP compared to healthy individuals, and increased with prolonged EOP duration, thus suggesting activation of the factors regulating immune system which promote suppression of the autoimmune process. The aim of this work was to study the dynamics of TGF-β1 and cytokine receptors: sTNFα-R1, sTNFα-R2, sIL-2R in the course of immunosuppressive therapy with high doses of GCs, as possible predictors of treatment efficacy. The study included 49 patients (98 eye orbits) with GD of euthyroid state and subclinical thyrotoxicosis, and the persons with EOP in active phase, who had not previously treatment for EOP. Concentrations of TGF-β1 cytokine, sTNFα-RI and sTNFα-R2, sIL-2R, antibodies to the thyroid-stimulating hormone receptor (rTSH), free fractions of thyroxine (fT4) and triiodothyronine (fT3), TSH in blood serum were determined in blood serum. Ultrasound examination of the thyroid gland (ultrasound of the thyroid gland), multi-layer computed tomography (MSCT)/magnetic resonance imaging (MRI) of the orbits were also performed. The patients were administered immunosuppressive therapy with high doses of HCs (methylprednisolone) in the course of pulse therapy, at a standard dosage of 4500-8000 mg, taking into account the severity and activity of the EOP clinical manifestations. The examination was carried out 3, 6, 12 months after starting the treatment. 3 and 6 months after the GC administration, more than 30% of patients remained resistant to treatment. The levels of TGF-β1 did not change significantly in the patients with positive EOP dynamics. In the patients resistant to GC treatment, the level of TGF-β1 was significantly decreased compared with patients who showed positive clinical dynamics. The level of sNFR1 and sNFaR2 did not change significantly. There were no significant differences in the levels of antibodies to rTSH, thyroid hormones in the patients resistant to GC treatment and with positive dynamics.Immunosuppressive therapy with high-dose of methylprednisolone in pulse therapy regimen showed high efficacy and good tolerability, while some patients remain resistant to treatment. Lower levels of TGF-β1 cytokine at initial time and during the treatment allow usage of TGF-β1 levels as a biomarker of the activity of the process, treatment efficiency, and prognosis of the disease. Activation of TGF-β1, a fibroblast growth factor, may contribute to the development of fibrosis, strabismus, and diplopia.

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TGF-β Physiology as a Novel Therapeutic Target Regarding Autoimmune Thyroid Diseases: Where Do We Stand and What to Expect

Cited by 12 publications

References 69 publications

Evaluation of Epithelial–Mesenchymal Transition Markers in Autoimmune Thyroid Diseases

Evaluation of Epithelial–Mesenchymal Transition Markers in Autoimmune Thyroid Diseases

The Effect of Rho Kinase Inhibitors on In Vitro Human Orbital Preadipocytes

Transforming growth factor β1 (TGF-β1) in patients with endocrine ophthalmopathy and Graves’ disease: A predictor of treatment efficiency

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