Pentraxin-3 Is a TSH-Inducible Protein in Human Fibrocytes and Orbital Fibroblasts.
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.
Departments of Ophthalmology and Visual Sciences (H.W., S.J.A., R.F., T.J.S.), University of Michigan Medical School, Ann Arbor, Michigan 48105; Department of Ophthalmology (H.W., R.-L.W.), Shanghai Changzheng Hospital, Second Military Medical University, 200003 Shanghai, China; and Division of Metabolism (T.J.S.), Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105.
Hao
H
Wang
Departments of Ophthalmology and Visual Sciences (H.W., S.J.A., R.F., T.J.S.), University of Michigan Medical School, Ann Arbor, Michigan 48105; Department of Ophthalmology (H.W., R.-L.W.), Shanghai Changzheng Hospital, Second Military Medical University, 200003 Shanghai, China; and Division of Metabolism (T.J.S.), Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105.
Stephen J
SJ
Atkins
Departments of Ophthalmology and Visual Sciences (H.W., S.J.A., R.F., T.J.S.), University of Michigan Medical School, Ann Arbor, Michigan 48105; Department of Ophthalmology (H.W., R.-L.W.), Shanghai Changzheng Hospital, Second Military Medical University, 200003 Shanghai, China; and Division of Metabolism (T.J.S.), Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105.
Roshini
R
Fernando
Departments of Ophthalmology and Visual Sciences (H.W., S.J.A., R.F., T.J.S.), University of Michigan Medical School, Ann Arbor, Michigan 48105; Department of Ophthalmology (H.W., R.-L.W.), Shanghai Changzheng Hospital, Second Military Medical University, 200003 Shanghai, China; and Division of Metabolism (T.J.S.), Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105.
Rui-Li
RL
Wei
Departments of Ophthalmology and Visual Sciences (H.W., S.J.A., R.F., T.J.S.), University of Michigan Medical School, Ann Arbor, Michigan 48105; Department of Ophthalmology (H.W., R.-L.W.), Shanghai Changzheng Hospital, Second Military Medical University, 200003 Shanghai, China; and Division of Metabolism (T.J.S.), Endocrinology, and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48105.
Terry J
TJ
Smith
D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology; D049970:Graves Ophthalmopathy / Q000378:metabolism; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011989:Receptors, Thyrotropin / Q000378:metabolism*; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013972:Thyrotropin / Q000494:pharmacology*; D000099153:Pentraxins
D002097:C-Reactive Protein; D003907:Dexamethasone; D005938:Glucocorticoids; D011989:Receptors, Thyrotropin; D000683:Serum Amyloid P-Component; D013972:Thyrotropin; D000099153:Pentraxins