- 作者: Mohamed F Salama, Henry K Bayele and Surjit SK Srai
- 作者服務機構: Department of Structural and Molecular Biology, Division of Biosciences, University College London, Gower Street, London, UK
- 中文摘要: --
- 英文摘要:
Background: Iron homeostasis is chiefly regulated by hepcidin; expression of which is tightly controlled by inflammation, iron stores, and hypoxia. Hemojuvelin (HJV) is a bone morphogenetic protein co-receptor that has been identified as a main upstream regulator of hepcidin expression; HJV mutations are associated with a severe form of iron overload (Juvenile haemochromatosis). Currently however, there is no information on how HJV is regulated by inflammation.
Methods: To study the regulation of Hjv expression by inflammation and whether Hfe has a role in that regulation, control and LPS-injected wild type and Hfe KO mice were used. Moreover, human hepatoma cells (HuH7) were used to study the effect of IL-6 and TNF-alpha on HJV mRNA expression.
Results: Here we show that LPS repressed hepatic Hjv and BMPs, while it induced hepcidin 1 expression in wild-type and Hfe KO mice with no effect on hepatic pSMAD 1, 5, 8 protein levels. In addition, exogenous TNF-alpha (20 ng/mL) decreased HJV mRNA and protein expression to 40% of control with no effect on hepcidin mRNA expression in 24 hours. On the other hand, IL-6 induced hepcidin mRNA and protein expression with no effect on HJV mRNA expression levels. Moreover, using the HJV promoter-luciferase reporter fusion construct (HJVP1.2-luc), we showed that the basal luciferase activity of HJVP1.2-luc was inhibited by 33% following TNF-alpha treatment of HuH7 transfected cells suggesting that the TNF-alpha down-regulation is exerted at the transcriptional level. Additionally, mutation of a canonical TNF- alpha responsive element (TNFRE) within HJVP1.2-luc abolished TNF-alpha response suggesting that this TNFRE is functional.
Conclusions: From these results, we conclude that TNF-alpha suppresses HJV transcription possibly via a novel TNFRE within the HJV promoter. In addition, the results suggest that the proposed link between inflammation and BMP-SMAD signalling is downstream of HJV and BMP ligands. - 中文關鍵字: --
- 英文關鍵字: Inflammation, Hemojuvelin, TNF-α