title: How one TSH receptor antibody induces thyrocyte proliferation while another induces apoptosis.
abstract: Thyroid stimulating hormone (TSH) activates two major G-protein arms, Gsα and Gq leading to initiation of down-stream signaling cascades for survival, proliferation and production of thyroid hormones. Antibodies to the TSH receptor (TSHR-Abs), found in patients with Graves' disease, may have stimulating, blocking, or neutral actions on the thyroid cell. We have shown previously that such TSHR-Abs are distinct signaling imprints after binding to the TSHR and that such events can have variable functional consequences for the cell. In particular, there is a great contrast between stimulating (S) TSHR-Abs, which induce thyroid hormone synthesis and secretion as well as thyroid cell proliferation, compared to so called "neutral" (N) TSHR-Abs which may induce thyroid cell apoptosis via reactive oxygen species (ROS) generation. In the present study, using a rat thyrocyte (FRTL-5) ex vivo model system, our hypothesis was that while N-TSHR-Abs can induce apoptosis via activation of mitochondrial ROS (mROS), the S-TSHR-Abs are able to stimulate cell survival and avoid apoptosis by actively suppressing mROS. Using fluorescent microscopy, fluorometry, live cell imaging, immunohistochemistry and immunoblot assays, we have observed that S-TSHR-Abs do indeed suppress mROS and cellular stress and this suppression is exerted via activation of the PKA/CREB and AKT/mTOR/S6K signaling cascades. Activation of these signaling cascades, with the suppression of mROS, initiated cell proliferation. In sharp contrast, a failure to activate these signaling cascades with increased activation of mROS induced by N-TSHR-Abs resulted in thyroid cell apoptosis. Our current findings indicated that signaling diversity induced by different TSHR-Abs regulated thyroid cell fate. While S-TSHR-Abs may rescue cells from apoptosis and induce thyrocyte proliferation, N-TSHR-Abs aggravate the local inflammatory infiltrate within the thyroid gland, or in the retro-orbit, by inducing cellular apoptosis; a phenomenon known to activate innate and by-stander immune-reactivity via DNA release from the apoptotic cells.
authors: Thyroid Research Unit, Icahn School of Medicine at Mount Sinai, and James J. Peters VA Medical Center, New York, NY, USA. Electronic address: syed.morshed@mssm.edu.
authors: Syed A
authors: SA
authors: Morshed
authors: Risheng
authors: R
authors: Ma
authors: Rauf
authors: R
authors: Latif
authors: Terry F
authors: TF
authors: Davies
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D050882:CREB-Binding Protein / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006111:Graves Disease / Q000276:immunology*; D006801:Humans; D018828:Immunoglobulins, Thyroid-Stimulating / Q000276:immunology*; D008928:Mitochondria / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018828:Immunoglobulins, Thyroid-Stimulating; D017382:Reactive Oxygen Species; D011989:Receptors, Thyrotropin; C094372:thyrotropin-binding inhibitory immunoglobulin; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Antibodies; Apoptosis; Proliferation; ROS-signaling; TSH receptor; Thyrocyte
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