Differential requirement of signal transducer and activator of transcription-4 (Stat4) and Stat6 in a thyrotropin receptor-289-adenovirus- induced model of Graves' hyperthyroidism

Kimberly J. Land, Prathyusha Gudapati, Mark Kaplan, Gattadahalli Seetharamaiah

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19 Citations (Scopus)

Abstract

T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4-/- mice, which lack Th1 cells, are susceptible, whereas Stat6-/- mice, which lack Th2 cells, are resistant to the induction of Graves' hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4 -/-, and Stat6-/- mice with an adenovirus expressing amino acid residues 1-289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4-/-, and 39% of Stat6-/- mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4-/- mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6-/- mice. BALB/c and Stat4-/ mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6-/- mice. In contrast, Stat6-/- mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-γ than BALB/c and Stat4-/- mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves' hyperthyroidism.

Original languageEnglish
Pages (from-to)111-119
Number of pages9
JournalEndocrinology
Volume147
Issue number1
DOIs
StatePublished - Jan 2006

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STAT4 Transcription Factor
Thyrotropin Receptors
Hyperthyroidism
Adenoviridae
Th2 Cells
Th1 Cells
Thyroid Gland
HEK293 Cells
Incidence
Humoral Immunity

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

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title = "Differential requirement of signal transducer and activator of transcription-4 (Stat4) and Stat6 in a thyrotropin receptor-289-adenovirus- induced model of Graves' hyperthyroidism",
abstract = "T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4-/- mice, which lack Th1 cells, are susceptible, whereas Stat6-/- mice, which lack Th2 cells, are resistant to the induction of Graves' hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4 -/-, and Stat6-/- mice with an adenovirus expressing amino acid residues 1-289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56{\%} of wild-type, 75{\%} of Stat4-/-, and 39{\%} of Stat6-/- mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4-/- mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6-/- mice. BALB/c and Stat4-/ mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6-/- mice. In contrast, Stat6-/- mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-γ than BALB/c and Stat4-/- mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves' hyperthyroidism.",
author = "Land, {Kimberly J.} and Prathyusha Gudapati and Mark Kaplan and Gattadahalli Seetharamaiah",
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T1 - Differential requirement of signal transducer and activator of transcription-4 (Stat4) and Stat6 in a thyrotropin receptor-289-adenovirus- induced model of Graves' hyperthyroidism

AU - Land, Kimberly J.

AU - Gudapati, Prathyusha

AU - Kaplan, Mark

AU - Seetharamaiah, Gattadahalli

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N2 - T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4-/- mice, which lack Th1 cells, are susceptible, whereas Stat6-/- mice, which lack Th2 cells, are resistant to the induction of Graves' hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4 -/-, and Stat6-/- mice with an adenovirus expressing amino acid residues 1-289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4-/-, and 39% of Stat6-/- mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4-/- mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6-/- mice. BALB/c and Stat4-/ mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6-/- mice. In contrast, Stat6-/- mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-γ than BALB/c and Stat4-/- mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves' hyperthyroidism.

AB - T helper type 1 (Th1) and Th2 cells have critical roles in the development of cell-mediated and humoral immune responses, respectively. This division of function predicts that Th1 cells mediate inflammatory diseases and Th2 cells promote antibody (Ab)-mediated autoimmunity. Our previous studies using HEK-293 cells expressing the extracellular domain of the TSH receptor (TSHR) showed that Stat4-/- mice, which lack Th1 cells, are susceptible, whereas Stat6-/- mice, which lack Th2 cells, are resistant to the induction of Graves' hyperthyroidism. To investigate the role of Stat4 and Stat6 genes in other murine models of hyperthyroidism, we injected wild-type BALB/c, Stat4 -/-, and Stat6-/- mice with an adenovirus expressing amino acid residues 1-289 of TSHR (TSHR-289-ad or 289-ad). The viral system induces a much stronger immune response with much more rapid onset of disease. Our results showed that 56% of wild-type, 75% of Stat4-/-, and 39% of Stat6-/- mice developed hyperthyroidism. Hyperthyroid mice exhibited thyroid stimulatory Abs. The Stat4-/- mice developed a higher incidence and greater severity of hyperthyroidism compared with wild-type and Stat6-/- mice. BALB/c and Stat4-/ mice showed significantly higher TSHR Abs of the IgG1 subclass and IL-4 compared with Stat6-/- mice. In contrast, Stat6-/- mice had predominantly the IgG2a subclass of TSHR Ab and produced significantly higher amounts of IFN-γ than BALB/c and Stat4-/- mice. All hyperthyroid mice showed enlarged thyroid glands with hyperactivity. These results suggest that in the TSHR-289-ad model, the Th2 cells are more efficient in mediating disease, but in the absence of Th2 cells, Th1 cells may still initiate a reduced incidence of Graves' hyperthyroidism.

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