TGF-beta promotes thyroid epithelial cell hyperplasia and fibrosis in IFN-gamma-deficient NOD.H-2h4 mice.
IFN-gamma(-/-)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-gamma(-/-) mice with TEC H/P produce TGF-beta 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-gamma(-/-) mice with severe TEC H/P transfer severe TEC H/P to IFN-gamma(-/-)NOD.H-2h4.SCID mice. Mice given anti-TGF-beta had markedly reduced thyrocyte proliferation and decreased fibrosis compared with mouse Ig-treated controls, suggesting that TGF-beta plays an important role in development of TEC H/P induced by activated splenocytes. Moreover, transgenic IFN-gamma(-/-)NOD.H-2h4 mice expressing TGF-beta on thyrocytes all develop fibrosis and moderate to severe TEC H/P with accelerated kinetics, directly demonstrating a role for TGF-beta in severe TEC H/P and fibrosis.
Yu
Shiguang
S
Department of Veterans Affairs Research Service, Columbia, MO 65212, USA.
Sharp
Gordon C
GC
Braley-Mullen
Helen
H
D000818:Animals; D000906:Antibodies / Q000276:immunology; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013952:Thymus Hyperplasia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II