Sphingosine-1-phosphate is involved in inflammatory reactions in patients with Graves’ orbitopathy

Seo, Yutaek; Chae, Min Kyung; Han, Sol Ah; Lee, Mi Kyung; Lee, Joon‐Hyung; Yoon, Jin Sook

doi:10.1007/s00011-017-1037-3

Cited by 9 publications

(9 citation statements)

References 32 publications

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“…IL-1β increases the production of prostaglandin E2 and hyaluronan in orbital fibroblasts, resulting in orbital tissue expansion [1,2,21]. Our group has also shown that IL-1β exacerbates inflammatory reactions in GO orbital fibroblasts by upregulating sphingosine-1-phos-phate receptors, sphingosine kinase, intercellular adhesion molecule-1, cyclooxygenase-2, and IL-6 [22]. Previous studies have found that CCL2, CXCL9, CXCL10, and CXCL11 are upregulated in GO orbital fibroblasts by proinf lammatory cytokines [5,6].…”

Section: Discussionmentioning

confidence: 74%

Chemokine Expression during Adipogenesis and Inflammation in Orbital Fibroblasts from Patients with Graves' Orbitopathy

Lee

Choi

Yoon

2020

Korean J Ophthalmol

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Graves' orbitopathy (GO) is an autoreactive inflammatory disease that causes expansion of orbital adipose tissue and edema of extraocular muscles within the orbit [1-3]. Generation of antibodies against self-antigens such as thyroid-stimulating hormone receptor and insulin-like growth factor-1 receptor, inflammatory infiltration, and accumula-Purpose: Chemokines are involved in the pathogenesis of various autoimmune diseases, including Graves' orbitopathy (GO), but comprehensive analyses of the dynamics of these cytokines and their receptors in such diseases remain lacking. In this study, we investigated the expressions of chemokines and their receptors during adipogenesis and inflammation in primary cultured orbital fibroblasts from patients with GO. Methods: The messenger RNA (mRNA) expression levels of chemokines were compared between GO (n = 6) and non-GO (n = 5) orbital tissues by real-time polymerase chain reaction. After adipogenesis was induced in primary cultured orbital fibroblasts from patients with GO (n =5) and following stimulation with interleukin (IL)-1β and tumor necrosis factor (TNF)-α, the mRNA expression levels of chemokines and their receptors were analyzed. Results: Chemokines were significantly downregulated in GO orbital tissues compared to non-GO orbital tissues (p < 0.05). Adipogenesis resulted in a strong increase in mRNA expression levels of chemokines and their receptors at an early stage (day 1); however, expression levels started to decrease thereafter and, eventually, decreased to below basal levels at the end of adipogenesis (day 10). Following stimulation with IL-1β and TNF-α, the mRNA expression levels of chemokines and their receptors increased, showing different responses to various proinflammatory cytokines. Conclusions: Chemokines were strongly upregulated in the early phase of adipogenesis before decreasing continuously until the end of adipogenesis. Also, overt mature GO tissues showed reduced mRNA expression of chemokines compared to controls, which might indicate the existence of a shorter window for effective medical inflammatory treatment. The heightened levels of chemokines and their receptors observed after stimulation with IL-1β and TNF-α suggest a crucial role of proinflammatory cytokines in the pathogenesis of GO and, further, support the idea that chemokines could be used as biomarkers of GO activity.

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Section: Discussionmentioning

confidence: 74%

Chemokine Expression during Adipogenesis and Inflammation in Orbital Fibroblasts from Patients with Graves' Orbitopathy

Lee

Choi

Yoon

2020

Korean J Ophthalmol

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“…S1P is involved in several diseases like cancer, 31 inflammatory bowel disease, 32 chronic kidney diseases, and multiple sclerosis. 33 Recently, it has been shown that S1P also plays a role in GO by promoting inflammation, 28 adipogenesis, 26 and fibrosis. 27 In our study we found increased S1P expression in the orbital adipose/connective tissue of GO patients.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the importance of S1P has been demonstrated in fibrosis, 27 adipogenesis, 26 and in the inflammatory reaction 28 in Graves' orbitopathy. It has also been demonstrated that mRNA for S1P receptors and SphK1/2 are upregulated after treatment with IL-1b, supporting our observations that proinflammatory events activate S1P formation.…”

Section: Discussionmentioning

confidence: 99%

“…25 Recently, it has been shown that S1P is involved in GO by promoting inflammation, adipogenesis, and fibrosis. [26][27][28] In this study we investigated the role of S1P produced by orbital fibroblasts in T-cell trafficking in GO. Our studies demonstrated that CD40 ligation stimulates GO fibroblast to produce S1P, which in turn triggers T-cell migration into orbital tissues.…”

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confidence: 99%

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CD40 Enhances Sphingolipids in Orbital Fibroblasts: Potential Role of Sphingosine-1-Phosphate in Inflammatory T-Cell Migration in Graves' Orbitopathy

Plöhn

Edelmann

Japtok

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation. METHODS. OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. RESULTS. GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. CONCLUSIONS. The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management.

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“…In addition, the role of S1P on adipogenesis and fibrosis [29,30] and in pro-inflammatory responses has been demonstrated. More specifically, IL-1β enhanced the expression of S1P receptors and sphingosine kinase in GO orbital fibroblasts; this in turn increased the expression of other pro-inflammatory mediators, including ICAM-1, COX-2, and IL-6 proteins [31].…”

Section: Graves' Diseasementioning

confidence: 93%

Functional Lipids in Autoimmune Inflammatory Diseases

Dei

Roda

et al. 2020

IJMS

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Lipids are apolar small molecules known not only as components of cell membranes but also, in recent literature, as modulators of different biological functions. Herein, we focused on the bioactive lipids that can influence the immune responses and inflammatory processes regulating vascular hyperreactivity, pain, leukocyte trafficking, and clearance. In the case of excessive pro-inflammatory lipid activity, these lipids also contribute to the transition from acute to chronic inflammation. Based on their biochemical function, these lipids can be divided into different families, including eicosanoids, specialized pro-resolving mediators, lysoglycerophospholipids, sphingolipids, and endocannabinoids. These bioactive lipids are involved in all phases of the inflammatory process and the pathophysiology of different chronic autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type-1 diabetes, and systemic lupus erythematosus.

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Sphingosine-1-phosphate is involved in inflammatory reactions in patients with Graves’ orbitopathy

Abstract: S1P has an important role in the pathological inflammatory process of GO, which is mediated through the SphK1-S1P- S1P receptor pathway. SphK1 inhibitors and S1P receptors or antagonists could be potential approaches for controlling the inflammatory process of GO.

Cited by 9 publications

References 32 publications

Chemokine Expression during Adipogenesis and Inflammation in Orbital Fibroblasts from Patients with Graves' Orbitopathy

Chemokine Expression during Adipogenesis and Inflammation in Orbital Fibroblasts from Patients with Graves' Orbitopathy

CD40 Enhances Sphingolipids in Orbital Fibroblasts: Potential Role of Sphingosine-1-Phosphate in Inflammatory T-Cell Migration in Graves' Orbitopathy

Functional Lipids in Autoimmune Inflammatory Diseases

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