IFN-γ inhibits and TGF-β promotes thyrocyte hyperplasia and proliferation (TEC H/P) by modulating pro- and anti-proliferative molecules (134.11)

Abstract

Abstract Our previous in vivo studies showed that IFN-γ-/-NOD.H-2h4 mice develop severe TEC H/P. Proliferating TEC produce TGF-β and IFN-γ inhibits TEC H/P. This study was undertaken to directly test the hypothesis that IFN-γ inhibits and TGF-β promotes TEC H/P in vitro and explore the underlying mechanisms. Varying concentrations of IFN-γ and TGF-β were incubated with cultured TEC for 3 days. Cell proliferation was evaluated by IHC staining for PCNA, while apoptosis was determined by TUNEL staining. RT-PCR was used to evaluate the effect of cytokines on pro- and anti-proliferative molecules. The results indicate that IFN-γ inhibits and TGF-β promotes TEC proliferation in a dose dependent manner, and both cytokines had little effect on apoptosis. The anti-proliferative effect of IFN-γ correlates with upregulation of the anti-proliferative molecule P21 and downregulation of pro-proliferative molecules cyclin D and PCNA. Studies to determine the mechanisms by which TGF-β promotes TEC H/P are in progress. These in vitro results are consistent with our previous in vivo studies and provide direct support for the hypothesis that IFN-γ inhibits, while TGF-β promotes, TEC H/P. This extends our previous study by providing evidence that cytokines regulate TEC H/P by modulating pro- and anti-proliferative molecules. Such studies may increase our understanding of mechanisms underlying development of epithelial cell hyperplasia in the thyroid as well as other tissues and organs (NIH RO1 AI074857).