TGF-beta-like transcriptional effects of thyroglobulin (Tg) in mouse mesangial cells.
TGF-beta-like activities of proteins unrelated to the cytokine could mimic its actions in fibrosis and cell proliferation. Thyroglobulin (Tg) has been identified as having a TGF-beta receptor (TGFbetaR)-binding activity and is deposited in the glomerulus in certain immune-complex diseases. The aim of the present study is to determine whether Tg can reproduce the transcriptional activity of TGF-beta1 in the mouse glomerular mesangial cell (MC), and to examine whether such activity is manifested through TGFbetaR. Real-time RT-PCR was employed to examine the effects of TGF-beta1 and bovine Tg on the expression of three genes (TGF-beta1, plasminogen activator inhibitor 1 [PAI-1], and Pax-8) regulated by TGF-beta1 in other cell types. In addition, a pentacosapeptide TGF-beta1 antagonist, beta(1)(25) (41-65) was employed to determine whether the transcriptional activity of Tg was mediated through the TGF-beta binding site on the TGFbetaR. A 6h exposure to TGF-beta1 resulted in increased TGF-beta1 and PAI-1 transcript, and a decrease in Pax-8. Similarly, a 6h exposure to Tg resulted in increases of about 5-fold in TGF-beta1 and PAI-1 mRNA and a decrease of 53% in Pax-8. In comparison with other proteins, Tg had the greatest positive effect on TGF-beta1 transcript levels. beta(1)(25) (41-65) significantly reduced the TGF-beta1-, but not the Tg-induced changes in TGF-beta1, PAI-1 and Pax-8 transcript levels. We conclude from these studies that Tg possesses a TGF-beta-mimetic transcriptional activity in the MC that is not mediated by its binding to TGFbetaR. These results suggest that Tg and other proteins could initiate glomerular injury by reproducing the actions of TGF-beta1 in the mesangial cell.
Sellitti
Donald F
DF
Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA.
Puggina
Enrico
E
Lagranha
Claudia
C
Doi
Sonia  Q
S
Pithon-Curi
Tania
T
Kohn
Leonard D
LD
Suzuki
Koichi
K
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D058258:Serpin E2; D015843:Serpins / Q000235:genetics; D013954:Thyroglobulin / Q000494:pharmacology* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics
D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D010446:Peptide Fragments; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013954:Thyroglobulin