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We have shown that thyroglobulin (Tg) is a potent autocrine regulator of thyroid-specific gene expression, and proposed that the accumulated follicular Tg within the colloid is a major factor in determining follicular function. In the present report, we examined the effect of Tg on the action of TSH/cAMP and iodine with special focus on the regulation of basolateral and apical iodide transporters; the sodium/iodide symporter (NIS) and the pendred syndrome gene (PDS) by Tg. We show that expression of NIS and PDS are differentially regulated by Tg concentration and exposure time. In addition, we found that PDS gene was induced by TSH/cAMP and iodide in the presence of Tg. Based on these results, we propose a model for the physiological turnover of follicular function that is dynamically regulated by Tg.
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
Search for other papers by Aimee D Kohn in
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
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Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, South Korea
The Howard Hughes Medical Institute and
The Department of Hematology, University of Washington, Seattle, Washington 98195, USA
Search for other papers by Leonard D Kohn in
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Wnt binding to cell surface receptors can activate a ‘canonical’ pathway that increases cellular β-catenin or a ‘noncanonical’ Ca++ pathway which can increase protein kinase C (PKC) activity. Although components of both Wnt/β-catenin-signaling pathways exist in thyrocytes, their biological role is largely unknown. In evaluating the biological role of Wnt signaling in differentiated FRTL-5 thyroid cells, we showed that TSH increased canonical Wnt-1 but, surprisingly, decreased the active form of β-catenin. Transient overexpression of Wnt-1 or β-catenin in FRTL-5 cells increased active β-catenin (ABC), decreased thyroperoxidase (TPO) mRNA, and suppressed TPO-promoter activity. The target of β-catenin suppressive action was a consensus T cell factor/lymphoid enhancing factor (TCF/LEF)-binding site 5′-A/T A/T CAAAG-3′, −137 to −129 bp on the rat TPO promoter. β-Catenin overexpression significantly increased complex formation between β-catenin/TCF-1 and an oligonucleotide containing the TCF/LEF sequence, suggesting that the β-catenin/TCF-1 complex acts as a transcriptional repressor of the TPO gene. Stable over-expression of Wnt-1 in FRTL-5 cells significantly increased the growth rate without increasing β-catenin levels. Increased growth was blunted by a PKC inhibitor, staurosporin. Wnt-1 overexpression increased serine phosphorylation, without affecting tyrosine phosphorylation, of signal transducers and activators of transcription 3 (STAT3) protein. In addition, these final results suggest that TSH-induced increase in Wnt-1 levels in thyrocytes contributes to enhanced cellular growth via a PKC pathway that increases STAT3 serine phosphorylation and activation, whereas TSH-induced decrease in activation of β-catenin simultaneously relieves transcriptional suppression of TPO. We hypothesize that Wnt signaling contributes to the ability of TSH to simultaneously increase cell growth and functional, thyroid-specific, gene expression.
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Search for other papers by Leonard D Kohn in
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Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
Department of Specialty Medicine, Appalachian Rural Health Institute, Edison Biotechnology Institute, Department of Biomedical Sciences, Biomedical Engineering Program, Interthyr Corporation, Diabetes Research Center
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Visceral adipocytes and associated macrophages produce and release excessive amounts of biologically active inflammatory cytokines via the portal and systemic vascular system, which induce insulin resistance in insulin target tissues such as fat, liver, and muscle. Free fatty acids (FFAs) absorbed via the portal system or released from adipocytes also induce insulin resistance. In this report, we show that phenylmethimazole (C10) blocks basal IL6 and leptin production as well as basal Socs-3 expression in fully differentiated 3T3L1 cells (3T3L1 adipocytes) without affecting insulin-stimulated AKT signaling. In addition, C10 inhibits palmitate-induced IL6 and iNos up-regulation in both 3T3L1 adipocytes and RAW 264.7 macrophages, LPS-induced NF-κB and IFN-β activation in 3T3L1 cells, and LPS-induced iNos, Ifn- β, Il1 β, Cxcl10, and Il6 expression in RAW 264.7 macrophages. C10 also blocks palmitate-induced Socs-3 up-regulation and insulin receptor substrate-1 (IRS-1) serine 307 phosphorylation in 3T3L1 adipocytes. Additionally, we show for the first time that although palmitate increases IRS-1 serine 307 phosphorylation in 3T3L1 adipocytes, AKT serine 473 phosphorylation is enhanced, not reduced, by palmitate. These results suggest that through inhibition of FFA-mediated signaling in adipocytes and associated macrophages, as well as possibly other insulin target cells/tissues (i.e. non-immune cells), C10 might be efficacious to prevent or reverse cytokine-induced insulin resistance seen in obesity-related insulin resistance and type 2 diabetes mellitus.
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Increased expression of major histocompatibility complex (MHC) class-I genes and aberrant expression of MHC class-II genes in thyroid epithelial cells (TECs) are associated with autoimmune thyroid diseases. Previous studies have shown that methimazole (MMI) reduces MHC class-I expression and inhibits interferon-γ (IFN-γ or IFNG as listed in the MGI Database)-induced expression of the MHC class-II genes in TECs. The action of MMI on the MHC class-I genes is transcriptional, but its mechanism has not been investigated previously. In the present study, we show that in Fisher rat thyroid cell line 5 cells, the ability of MMI and its novel derivative phenylmethimazole (C10) to decrease MHC class-I promoter activity is similar to TSH/cAMP suppression of MHC class-I and TSH receptor genes, and involves a 39 bp silencer containing a cAMP response element (CRE)-like site. Furthermore, we show that C10 decreases MHC class-I gene expression to a greater extent than MMI and at 10- to 50-fold lower concentrations. C10 also reduces the IFN-γ-induced increase in the expression of MHC class-I and MHC class-II genes more effectively than MMI. Finally, we show that in comparison to MMI, C10 is a better inhibitor of specific protein–DNA complexes that are formed with a CRE-like element on the MHC class-II promoter. These data support the conclusion that the immunosuppressive mechanism by which MMI and C10 inhibit MHC gene expression mimics ‘normal’ hormonal suppression by TSH/cAMP.
