TSH receptor-adenovirus-induced Graves' hyperthyroidism is attenuated in both interferon-gamma and interleukin-4...

The role of the Th1/Th2 balance in the pathogenesis of murine Graves' hyperthyroidism is controversial. In BALB/c mice injected with adenovirus expressing TSH receptor (TSHR-adeno model), we found that suppression of TSHR-specific Th1 immune responses by exogenous interleukin-4 (IL-4), alpha-galactosylceramide or helminth (Schistosoma mansoni) infection was associated with inhibition of hyperthyroidism, indicating the critical role for Th1 cytokines. In contrast, BALB/c IL-4 knockout (KO), but not interferon-gamma (IFN-gamma) KO mice failed to develop Graves' hyperthyroidism when injected with TSHR-expressing M12 B lymphoma cells (TSHR-M12 model), suggesting the importance of Th2 cytokine IL-4. To reconcile differences in these two models, we used IL-4 KO and IFN-gamma KO BALB/c mice in the TSHR-adeno model. Unlike wild-type (wt) BALB/c mice in which 60% developed hyperthyroidism, only 13 and 7% of IL-4 KO and IFN-gamma KO mice, respectively, became hyperthyroid. Thyroid stimulating antibodies were positive in most hyperthyroid mice. TSHR antibody titres determined by TSH binding inhibition and ELISA were comparable in all three groups. IgG1 and IgG2a TSHR antibody titres were similar in IFN-gamma KO and wt mice, whereas IgG1 TSHR antibody titres and TSHR-specific splenocyte IFN-gamma secretion were lower in IL-4 KO than in IFN-gamma KO and wt mice, respectively. Our results clearly implicate both IFN-gamma and IL-4 in development of hyperthyroidism in the TSHR-adeno model. These data, together with the previous report, also indicate different cytokine requirements in these two Graves' models, with IFN-gamma being more important in the TSHR-adeno than the TSHR-M12 model. Moreover, our previous and present observations indicate a difference in the role of exogenous versus endogenous IL-4 in TSHR-adenovirus induced Graves' hyperthyroidism.