Abstract
ContextFibrocytes appear to participate in inflammation and tissue remodeling in patients with thyroid-associated ophthalmopathy (TAO). These patients have increased frequencies of circulating TSH receptor (TSHR)- and CD40-positive fibrocytes, suggesting TSHR and CD40 may play roles in proinflammatory cytokine production, which ultimately leads to orbital inflammation and tissue remodeling.ObjectiveTo investigate the potential interactions between the TSHR and CD40 signaling pathways and their roles in IL-6 and TNF-α production.Design and Outcome MeasuresCD40 expression on fibrocytes was assessed using flow cytometry; IL-6 and TNF-α protein release using Luminex technology; increased IL-6 and TNF-α mRNA abundance, using real-time PCR; TSH- and CD40 ligand (CD40L)-stimulated Akt phosphorylation in fibrocytes, by western blot analysis; TSHR-CD40 protein-protein interaction, using co-immunoprecipitation, and CD40-TSHR co-localization, using immunocytochemistry.ResultsTSH enhances CD40 expression at a pre-translational level in fibrocytes. Production of IL-6 and TNF-α after costimulation with TSH and CD40L was greater than that after TSH or CD40L stimulation alone. TSH and CD40L costimulation also resulted in greater Akt phosphorylation. Akt and nuclear factor (NF)-κB inhibitors significantly reduced cytokine production after TSH and CD40L costimulation. TSHR and CD40L are colocalized on the cell surface and form a complex.ConclusionsTSHR and CD40 in fibrocytes appear to be physically and functionally related. TSH stimulates CD40 production on the fibrocyte surface. Cytokine expression upon simultaneous stimulation of TSHR and CD40 is greater than levels achieved with TSH or CD40L alone. Increased expression of CD40 by TSH is a potential mechanism for this process.
Highlights
Graves’ disease (GD) is typically characterized by circulating autoantibodies, thyrotoxicosis, and often, orbital inflammation, and orbit remodeling
Cytokine expression upon simultaneous stimulation of TSH receptor (TSHR) and CD40 is greater than levels achieved with TSH or CD40 ligand (CD40L) alone
Increased expression of CD40 by TSH is a potential mechanism for this process
Summary
Graves’ disease (GD) is typically characterized by circulating autoantibodies, thyrotoxicosis, and often, orbital inflammation, and orbit remodeling. Antibodies to the TSH receptor (TSHR) stimulate thyroid hormone production by activating this receptor on thyroid epithelial cells resulting in hyperthyroidism.[1] TSHR activation is a central component of GD. A growing body of evidence indicates that orbital fibroblasts (OFs) play an important role in the pathology of the disease by interacting with infiltrating immune cells, such as T and B cells. Orbital fibroblasts from patients with TAO expresses CD40 while fibroblasts from patients with non-inflammatory conditions do not.[7] Increased CD40L expression has been observed in T cells derived from the plasma of patients with GD.[8] The CD40-CD40L interaction promotes the production of proinflammatory cytokines, including IL-8 and IL-6.[7] Orbital fibroblasts from patients with TAO produce cytokines (e.g. IL-6, and IL-8) in response to TSH stimulation, suggesting that circulating antibodies may directly support orbital inflammation. Orbital fibroblasts from patients with TAO produce cytokines (e.g. IL-6, and IL-8) in response to TSH stimulation, suggesting that circulating antibodies may directly support orbital inflammation. [9, 10]
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