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Thyrotropin Regulates IL-6 Expression in CD34(+) Fibrocytes: Clear Delineation of Its cAMP-Independent Actions

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...

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Autores principales: Raychaudhuri, Nupur, Fernando, Roshini, Smith, Terry J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783445/
https://www.ncbi.nlm.nih.gov/pubmed/24086448
http://dx.doi.org/10.1371/journal.pone.0075100
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author Raychaudhuri, Nupur
Fernando, Roshini
Smith, Terry J.
author_facet Raychaudhuri, Nupur
Fernando, Roshini
Smith, Terry J.
author_sort Raychaudhuri, Nupur
collection PubMed
description 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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spelling pubmed-37834452013-10-01 Thyrotropin Regulates IL-6 Expression in CD34(+) Fibrocytes: Clear Delineation of Its cAMP-Independent Actions Raychaudhuri, Nupur Fernando, Roshini Smith, Terry J. PLoS One Research Article 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. Public Library of Science 2013-09-25 /pmc/articles/PMC3783445/ /pubmed/24086448 http://dx.doi.org/10.1371/journal.pone.0075100 Text en © 2013 Raychaudhuri et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Raychaudhuri, Nupur
Fernando, Roshini
Smith, Terry J.
Thyrotropin Regulates IL-6 Expression in CD34(+) Fibrocytes: Clear Delineation of Its cAMP-Independent Actions
title Thyrotropin Regulates IL-6 Expression in CD34(+) Fibrocytes: Clear Delineation of Its cAMP-Independent Actions
title_full Thyrotropin Regulates IL-6 Expression in CD34(+) Fibrocytes: Clear Delineation of Its cAMP-Independent Actions
title_fullStr Thyrotropin Regulates IL-6 Expression in CD34(+) Fibrocytes: Clear Delineation of Its cAMP-Independent Actions
title_full_unstemmed Thyrotropin Regulates IL-6 Expression in CD34(+) Fibrocytes: Clear Delineation of Its cAMP-Independent Actions
title_short Thyrotropin Regulates IL-6 Expression in CD34(+) Fibrocytes: Clear Delineation of Its cAMP-Independent Actions
title_sort thyrotropin regulates il-6 expression in cd34(+) fibrocytes: clear delineation of its camp-independent actions
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783445/
https://www.ncbi.nlm.nih.gov/pubmed/24086448
http://dx.doi.org/10.1371/journal.pone.0075100
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