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TGF-β Promotes Thyroid Epithelial Cell Hyperplasia and Fibrosis in IFN--Deficient NOD.H-2h4 Mice¹

Shiguang Yu^*,, Gordon C. Sharp^, and Helen Braley-Mullen^2,*,,

^* Department of Veterans Affairs Research Service, Columbia, MO 65212; and Department of Internal Medicine, Department of Pathology, and Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO 65212

IFN-^–/–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-^–/– 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-^–/– mice with severe TEC H/P transfer severe TEC H/P to IFN-^–/–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-^–/–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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a Merit Review Grant from the Department of Veterans Affairs, the A. P. Green Foundation, the University of Missouri Research Council, and the University of Missouri Research Board.

² Address correspondence and reprint requests to Dr. Helen Braley-Mullen, Division of Immunology and Rheumatology, Department of Internal Medicine, University of Missouri, M307 Health Science Center, One Hospital Drive, Columbia, MO 65212. E-mail address: mullenh{at}health.missouri.edu

³ Abbreviations used in this paper: SAT, spontaneous autoimmune thyroiditis; L-SAT, lymphocytic SAT; TEC H/P, thyroid epithelial cell hyperplasia and proliferation; p-Smad, phosphorylated Smad; Tg, transgenic; WT, wild type; RTg, rat thyroglobulin; ISH, in situ hybridization; TβR II, TGF-β receptor II.