Differential requirement of signal transducer and activator of transcription-4 (Stat4) and Stat6 in a thyrotropin receptor-289-adenovirus-induced model of Graves' hyperthyroidism.
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.
Land
Kimberly J
KJ
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Evansville, Indiana 47712, USA.
Gudapati
Prathyusha
P
Kaplan
Mark H
MH
Seetharamaiah
Gattadahalli S
GS
D000256:Adenoviridae; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D006111:Graves Disease / Q000503:physiopathology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007668:Kidney; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011989:Receptors, Thyrotropin / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics*; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics*
D011989:Receptors, Thyrotropin; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D007371:Interferon-gamma