TGF-1β Promotes Proliferation of Thyroid Epithelial Cells in IFN-γ-/- Mice by Down-Regulation of p21 and p27 via AKT Pathway

IFN-gamma(-/-) NOD.H-2h4 mice develop an autoimmune disease characterized by hyperplasia and proliferation of thyroid epithelial cells (TEC HIP). Proliferating TECs produce TGF-beta, and IFN-gamma inhibits TEC H/P. In the present study, cultured TECs were used to directly determine the mechanisms by which these cytokines act on TECs to result in proliferation or inhibition of proliferation. With TECs from IFN-gamma(-/-) NOD.H-2h4 mice or mice expressing the dominant negative TGF-beta type II receptor on TECs, TGF-beta was shown to promote TEC proliferation and IFN-gamma was shown to inhibit TEC proliferation in vitro. TGF-beta may promote TEC proliferation by down-regulating antiproliferative molecules p21 and p27, whereas IFN-gamma may inhibit proliferation by up-regulating antiproliferative molecules p18 and p21 and down-regulating the proproliferative molecule cyclin D. Inhibition of AKT abolished the effect of TGF-beta on p21 and p27, resulting in similar proliferation of TGF-beta-treated and control TECs. Increased expression of proliferating cell nuclear antigen (PCNA), TGF-beta, and p-AKT and decreased expression of p21 and p27 by proliferating TECs correlated with the proliferative state of TEC H/P. Taken together, the results suggest that TGF-beta promotes TEC proliferation by down-regulating p21 and p27 via the AKT pathway in IFN-gamma(-/-) NOD.H-2h4 mice, which may have significant implications for development of effective therapeutic strategies targeting the TGF-beta and AKT pathways for treatment of hyperplasia and/or neoplasia. Pathol 2012, 180: 650-660; DOI: 10.1016/j.ajpath.2011.10.009)