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-gamma 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.

• Authors: Kimberly J Land, Prathyusha Gudapati, Mark H Kaplan, Gattadahalli S Seetharamaiah
• Journal: Endocrinology (Endocrinology) Vol. 147 Issue 1 Pg. 111-9 (Jan 2006) ISSN: 0013-7227 [Print] United States
• PMID: 16195404 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Thyrotropin
• STAT4 Transcription Factor
• STAT6 Transcription Factor
• Stat4 protein, mouse
• Stat6 protein, mouse
• Interferon-gamma

Topics

• Adenoviridae
• Animals
• Cell Line
• Disease Models, Animal
• Graves Disease (physiopathology)
• Humans
• Interferon-gamma (genetics)
• Kidney
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Receptors, Thyrotropin (genetics)
• STAT4 Transcription Factor (deficiency, genetics)
• STAT6 Transcription Factor (deficiency, genetics)