ArticlePloS one2010
PGE2 induces IL-6 in orbital fibroblasts through EP2 receptors and increased gene promoter activity: implications to thyroid-associated ophthalmopathy.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 43 citations in OpenAlex.
- Integrative transcriptomic profiling and machine learning reveal hypoxia-associated molecular signatures for precision diagnosis in thyroid eye disease.Human genomics · 2025Article
- Inflammatory profiling and immune cell infiltration in dysthyroid optic neuropathy: insights from bulk RNA sequencing.Frontiers in immunology · 2025Article
- A Narrative Review: Immunometabolic Interactions of Host-Gut Microbiota and Botanical Active Ingredients in Gastrointestinal Cancers.International journal of molecular sciences · 2024Review
- Article
- Immunopathological events surrounding IL-6 and IFN-α: A bridge for anti-lupus erythematosus drugs used to treat COVID-19.International immunopharmacology · 2021Review
- Prostaglandin E2 Receptor 4 (EP4) Affects Trophoblast Functions via Activating the cAMP-PKA-pCREB Signaling Pathway at the Maternal-Fetal Interface in Unexplained Recurrent Miscarriage.International journal of molecular sciences · 2021Article
- Non-steroidal anti-inflammatory drugs, prostaglandins, and COVID-19.British journal of pharmacology · 2020Review
- The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy.Eye (London, England) · 2019Article
- Immunological Aspects of Graves' Ophthalmopathy.BioMed research international · 2019Review
- Chitosan inhibits inflammation and adipogenesis of orbital fibroblasts in Graves ophthalmopathy.Molecular vision · 2018Article
- Intraorbital Electroacupuncture Therapy for Thyroid-associated Ophthalmopathy.Chinese medical journal · 2017Article
- Article
- Myeloid Cell Prostaglandin E2 Receptor EP4 Modulates Cytokine Production but Not Atherogenesis in a Mouse Model of Type 1 Diabetes.PloS one · 2016Article
- Article
- CD40 Expression in Fibrocytes Is Induced by TSH: Potential Synergistic Immune Activation.PloS one · 2016Article
- Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment.Cell research · 2015Article
- TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy.Nature reviews. Endocrinology · 2015Review
- Thyroid-associated orbitopathy is linked to gastrointestinal autoimmunity.Clinical and experimental immunology · 2014Article
- PI3K/AKT pathway mediates induction of IL-1RA by TSH in fibrocytes: modulation by PTEN.The Journal of clinical endocrinology and metabolism · 2014Article
- Cytokines are both villains and potential therapeutic targets in thyroid-associated ophthalmopathy: From bench to bedside.Expert review of ophthalmology · 2014Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundIL-6 plays an important role in the pathogenesis of Graves' disease and its orbital component, thyroid-associated ophthalmopathy (TAO). Orbital tissues become inflamed in TAO, a process in which prostanoids have been implicated. Orbital fibroblasts both generate and respond to PGE(2), underlying the inflammatory phenotype of these cells. METHODOLOGY/PRINCIPAL
findingsUsing cultured orbital and dermal fibroblasts, we characterized the effects of PGE(2) on IL-6 expression. We found that the prostanoid provokes substantially greater cytokine synthesis in orbital fibroblasts, effects that are mediated through cell-surface EP(2) receptors and increased steady-state IL-6 mRNA levels. The pre-translational up-regulation of IL-6 results from increased gene promoter activity and can be reproduced with the PKA agonist, Sp-cAMP and blocked by interrupting the PKA pathway. PGE(2)-induced production of cAMP in orbital fibroblasts was far greater than that in dermal fibroblasts, resulting from higher levels of adenylate cyclase. PGE(2) provokes CREB phosphorylation, increases the pCREB/CREB ratio, and initiates nuclear localization of the pCREB/CREB binding protein/p300 complex (CBP) preferentially in orbital fibroblasts. Transfection with siRNAs targeting either CREB or CBP blunts the induction of IL-6 gene expression. PGE(2) promotes the binding of pCREB to its target DNA sequence which is substantially greater in orbital fibroblasts. CONCLUSION/SIGNIFICANCE: These results identify the mechanism underlying the exaggerated induction of IL-6 in orbital fibroblasts and tie together two proinflammatory pathways involved in the pathogenesis of TAO. Moreover, they might therefore define an attractive therapeutic target for the treatment of TAO.
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