Pentraxin-3 Is a TSH-Inducible Protein in Human Fibrocytes and Orbital Fibroblasts

Abstract

CD34(+) fibrocytes are bone marrow-derived monocyte progenitor cells that traffic to sites of tissue injury and repair. They putatively infiltrate the orbit in thyroid-associated ophthalmopathy where they appear to transition into CD34(+) orbital fibroblasts (OFs) that interact with residential CD34(-) fibroblasts. A unique phenotypic attribute of fibrocytes and CD34(+) OFs is their expression of the functional thyrotropin receptor (TSHR) and other "thyroid-specific" proteins. When activated through TSHR, fibrocytes express a number of cytokines and other inflammatory genes. Here we sought to determine whether pentraxin-3 (PTX-3), an acute-phase protein involved in inflammation and autoimmunity, might be induced by TSH in fibrocytes and OFs. These cells were collected from patients with Graves disease and healthy individuals. PTX-3 mRNA levels were determined by real-time PCR, protein was determined by ELISA and Western blot, and PTX-3 gene promoter activity was assessed with reporter assays. PTX-3 expression was induced by TSH in both cell types, regardless of the health status of the donor and was a consequence of increased steady-state PTX-3 mRNA levels. M22, a TSHR-activating monoclonal antibody, also induced PTX-3. The induction could be attenuated by dexamethasone and by IGF-I receptor-blocking antibodies, teprotumumab and 1H7. TSH effects were mediated through phosphatidylinositol 3-kinase/AKT, mammalian target of rapamycin/p70(s6k), Janus tyrosine kinase 2 pathways, and enhanced PTX-3 mRNA stability. These findings indicate that PTX-3 is a TSH target gene, the expression of which can be induced in fibrocytes and OFs. They suggest that PTX-3 might represent a previously unidentified nexus between the thyroid axis and the mechanisms involved in tissue remodeling.

PTX3: A Potential Biomarker in Thyroid Associated Ophthalmopathy

“…We also detected the accumulation of PTX3 protein in the orbital adipose-connective tissue of TAO patients. This approved what Planck et al [ 18 ] and Wang et al [ 19 ] found. Planck et al found a higher expression of PTX3 in orbital adipose tissue from patients with active TAO than those from healthy controls (fold change = 4.40; n = 10 : 10).…”

“…Planck et al found a higher expression of PTX3 in orbital adipose tissue from patients with active TAO than those from healthy controls (fold change = 4.40; n = 10 : 10). In Wang et al's study [ 19 ], the basal levels of PTX3 in orbital fibroblasts from patients with Graves' disease appeared to be higher than those from healthy controls ( p < 0.05). Wang et al also discovered that the addition of TSH and M22 (TSHR stimulating autoantibody) could stimulate PTX3 production in fibrocytes and orbital fibroblasts.…”

Reflections on Thyroid Autoimmunity: A Personal Overview from the Past into the Future

“…Remarkably, contrary to the need for development of antigen-specific therapy for GO, an ever-growing number of non-specific immune-related and signal transduction molecules are being proposed as potential targets for therapy in GO. Indeed, one laboratory in the past 4 years has published data on the following molecules described to be of interest in this regard; IL-1R antagonist, IL-6, IL-8, IL-12, IL-23/IL-17, TNF alpha, Slit2, CXCL-12/CXCR4, Pen-traxin-3, PTEN, AIRE, PCP-1, and p53 [101][102][103][104][105][106][107][108]. The modified Bill Clinton campaign slogan mentioned above deserves repeating.…”

CD34− Orbital Fibroblasts From Patients With Thyroid-Associated Ophthalmopathy Modulate TNF-α Expression in CD34+ Fibroblasts and Fibrocytes

“…4 B). Unlike its action on several cytokine-encoding mRNAs in fibrocytes, 22 , 23 bTSH failed to retard TNF-α mRNA degradation significantly. Thus, it would appear that TSH exerts its principal actions on TNF-α expression through enhanced gene transcription.…”