Abstract
Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to thyroid eye disease (TED). α-Melanocytemelanocyte-stimulating hormone (α-MSH) is a well-known tridecapeptidetreatment for several inflammatory disorders including sepsis syndrome, acute respiratory distress syndrome, rheumatoid arthritis, and encephalitis. Here, we investigated the effect of α-MSH treatment on TED. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays were performed to analyze the effect of α-MSH on cell viability and it’s toxicity. Using primary cultures of orbital fibroblasts from TED patients and non-TED as control, we examined the effects of α-MSH on proinflammatory cytokine production induced by interleukin (IL)-1β, further analyzed by real-time reverse transcription-polymerase chain reaction (qPCR) and western blotting. Immunofluorescence staining assay and qPCR were performed to examine proopiomelanocortin (POMC) expression, the upstream neuropeptide of α-MSH in TED patients and non-TED control. Treatment with non-cytotoxic concentrations of α-MSH resulted in the dose-dependent inhibition of mRNA and protein levels (p < 0.05) for IL-1β-induced inflammatory cytokines: IL-6, IL-8, MCP-1, ICAM-1, and COX-2. The expression of POMC mRNA and protein were significantly higher in TED patients compared to non-TED control (p < 0.05). Our data show significant inhibitory effects of α-MSH on inflammation, POMC production in orbital fibroblasts. At present, this is the first in vitro preclinical evidence of α-MSH therapeutic effect on TED. These findings indicate that POMC and α-MSH may play a role in the immune regulation of TED and can be a potential therapeutic target.
Highlights
Thyroid eye disease (TED), known as thyroid-related ophthalmopathy (TRO), Graves’s ophthalmopathy (GO), is an autoimmune inflammatory disease of the orbit [1,2]
Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy indicated that a population of orbital fibroblasts has been putatively traced to bone marrow–derived progenitor cells, known as fibrocytes which expressed CD45, CD34, CXCR4, collagen I, functional TSHR, and thyroglobulin (Tg) [19]
Fibrocytes increase in Graves’ disease (GD), we believe that fibrocytes might be linked to the orbit in thyroid-associated ophthalmopathy (TAO).The orbital fat primary culture from normal control and thyroid eye disease (TED) patients were flat and elongated in morphology
Summary
Thyroid eye disease (TED), known as thyroid-related ophthalmopathy (TRO), Graves’s ophthalmopathy (GO), is an autoimmune inflammatory disease of the orbit [1,2]. The inflammatory process in the orbit affects muscles, connective and adipose tissues at various degrees, which is responsible for the several clinical manifestations of the disease [3]. Previous research showed that TED is related to the abnormal secretion of inflammatory cytokines [5,6] These over-expressed inflammatory cytokines promoted the infiltration of thyroid lymphocytes and the activation of B cells, leading to the production of autoimmune antibodies against thyroid antigens during TED development [7]. The production of α-MSH is widespread and mainly generated by the pituitary, skin tissue, and immune cells [13], it’s anti-inflammatory and immunomodulatory properties have been the focus of study in recent years [14,15]. Understanding potential regulatory effect of TED may provide the fundamental basis for the different clinical manifestations of TED in the future
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