ArticlePloS one2013
Thyrotropin regulates IL-6 expression in CD34+ fibrocytes: clear delineation of its cAMP-independent actions.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 59 citations in OpenAlex.
- Probiotics and Prebiotics in Subclinical Hypothyroidism of Pregnancy with Small Intestinal Bacterial Overgrowth.Probiotics and antimicrobial proteins · 2024Trial
- The role of monoclonal antibodies against IL-6 or IL-6R in the treatment of thyroid eye disease.Reviews in endocrine & metabolic disorders · 2026Review
- Correlation between the reduction of IL-6 and TNF-α with muscle mass restoration in hyperthyroid patients post-radioactive iodine therapy.Frontiers in endocrinology · 2026Article
- Targeted Delivery of CD34 Aptamer-Coupled Tocilizumab Microspheres for Effective Treatment of Thyroid-Associated Ophthalmopathy.Investigative ophthalmology & visual science · 2025Article
- Determinants of clinical outcome in patients with moderate/severe Graves' orbitopathy undergoing treatment with parenteral glucocorticoids: a retrospective study.Frontiers in endocrinology · 2024Article
- Fibrocyte Participation in Thyroid-Associated Ophthalmopathy Suggests New Approaches to Therapy.Ophthalmic plastic and reconstructive surgery · 2023Review
- Possible molecular exploration of herbal pair Haizao-Kunbu in the treatment of Graves' disease by network pharmacology, molecular docking, and molecular dynamic analysis.Frontiers in endocrinology · 2023Article
- 2021 update on thyroid-associated ophthalmopathy.Journal of endocrinological investigation · 2022Review
- Cytokines in Thyroid-Associated Ophthalmopathy.Journal of immunology research · 2022Review
- Graves' Autoantibodies Exhibit Different Stimulating Activities in Cultures of Thyrocytes and Orbital Fibroblasts Not Reflected by Clinical Assays.Thyroid : official journal of the American Thyroid Association · 2022Article
- Therapeutic IGF-I receptor inhibition alters fibrocyte immune phenotype in thyroid-associated ophthalmopathy.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Teprotumumab Treatment for Thyroid-Associated Ophthalmopathy.European thyroid journal · 2020Article
- Slit2 May Underlie Divergent Induction by Thyrotropin of IL-23 and IL-12 in Human Fibrocytes.Journal of immunology (Baltimore, Md. : 1950) · 2020Article
- Teprotumumab as a Novel Therapy for Thyroid-Associated Ophthalmopathy.Frontiers in endocrinology · 2020Review
- Thyroid-associated ophthalmopathy: Emergence of teprotumumab as a promising medical therapy.Best practice & research. Clinical endocrinology & metabolism · 2020Review
- Will biological agents supplant systemic glucocorticoids as the first-line treatment for thyroid-associated ophthalmopathy?European journal of endocrinology · 2019Review
- TSHR Signaling Stimulates Proliferation Through PI3K/Akt and Induction of miR-146a and miR-155 in Thyroid Eye Disease Orbital Fibroblasts.Investigative ophthalmology & visual science · 2019Article
- Neutrophil extracellular traps and fibrocytes in ST-segment elevation myocardial infarction.Basic research in cardiology · 2019Article
- Potential Roles of CD34+ Fibrocytes Masquerading as Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy.The Journal of clinical endocrinology and metabolism · 2019Review
- Insulin-like Growth Factor-I Receptor and Thyroid-Associated Ophthalmopathy.Endocrine reviews · 2019Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
IL-6 plays diverse roles in normal and disease-associated immunity such as that associated with Graves' disease (GD). In that syndrome, the orbit undergoes remodeling during a process known as thyroid-associated ophthalmopathy (TAO). Recently, CD34(+) fibrocytes were found to infiltrate the orbit in TAO where they transition into CD34(+) orbital fibroblasts. Surprisingly, fibrocytes display high levels of functional thyrotropin receptor (TSHR), the central antigen in GD. We report here that TSH and the pathogenic anti-TSHR antibodies that drive hyperthyroidism in GD induce IL-6 expression in fibrocytes and orbital fibroblasts. Unlike TSHR signaling in thyroid epithelium, that occurring in fibrocytes is completely independent of adenylate cyclase activation and cAMP generation. Instead TSH activates PDK1 and both AKT/PKB and PKC pathways. Expression and use of PKCβII switches to that of PKCµ as fibrocytes transition to TAO orbital fibroblasts. This shift is imposed by CD34(-) orbital fibroblasts but reverts when CD34(+) fibroblasts are isolated. The up-regulation of IL-6 by TSH results from coordinately enhanced IL-6 gene promoter activity and increased IL-6 mRNA stability. TSH-dependent IL-6 expression requires activity at both CREB (-213 to -208 nt) and NF-κB (-78 to -62 nt) binding sites. These results provide novel insights into the molecular action of TSH and signaling downstream for TSHR in non-thyroid cells. Fibrocytes neither express adenylate cyclase nor generate cAMP and thus these findings are free from any influence of cAMP-related signaling. They identify potential therapeutic targets for TAO.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.