TGF-β Promotes Thyroid Epithelial Cell Hyperplasia and Fibrosis in IFN-γ-Deficient NOD.H-2h4 Mice

Abstract

IFN-γ−/−NOD.H-2h4 mice given 0.05% NaI in their water develop severe thyroid epithelial cell (thyrocyte) hyperplasia and proliferation (TEC H/P) and fibrosis. Proliferating thyrocytes of IFN-γ−/− mice with TEC H/P produce TGF-β as demonstrated by immunohistochemical staining and in situ hybridization. Strong expression of activating phosphorylated Smad-2/3 and weak expression of inhibitory Smad-7 by proliferating thyrocytes correlate with the severity of TEC H/P. Splenocytes from IFN-γ−/− mice with severe TEC H/P transfer severe TEC H/P to IFN-γ−/−NOD.H-2h4.SCID mice. Mice given anti-TGF-β had markedly reduced thyrocyte proliferation and decreased fibrosis compared with mouse Ig-treated controls, suggesting that TGF-β plays an important role in development of TEC H/P induced by activated splenocytes. Moreover, transgenic IFN-γ−/−NOD.H-2h4 mice expressing TGF-β on thyrocytes all develop fibrosis and moderate to severe TEC H/P with accelerated kinetics, directly demonstrating a role for TGF-β in severe TEC H/P and fibrosis.