Tumour necrosis factor alpha downregulates human hemojuvelin expression via a novel response element within its promoter
<p>Abstract</p> <p>Background</p> <p>Iron homeostasis is chiefly regulated by hepcidin whose expression 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 upst...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2012-09-01
|
| Series: | Journal of Biomedical Science |
| Subjects: | |
| Online Access: | http://www.jbiomedsci.com/content/19/1/83 |
| Summary: | <p>Abstract</p> <p>Background</p> <p>Iron homeostasis is chiefly regulated by hepcidin whose expression 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 <it>hepcidin</it> expression; <it>HJV</it> mutations are associated with a severe form of iron overload (Juvenile haemochromatosis). Currently however, there is no information on how <it>HJV</it> is regulated by inflammation.</p> <p>Methods</p> <p>To study the regulation of <it>Hjv</it> expression by inflammation and whether Hfe has a role in that regulation, control and LPS-injected wild type and <it>Hfe</it> KO mice were used. Moreover, human hepatoma cells (HuH7) were used to study the effect of IL-6 and TNF-α on <it>HJV</it> mRNA expression.</p> <p>Results</p> <p>Here we show that LPS repressed hepatic <it>Hjv</it> and <it>BMPs</it>, while it induced <it>hepcidin</it> 1 expression in wild-type and <it>Hfe</it> KO mice with no effect on hepatic pSMAD 1, 5, 8 protein levels. In addition, exogenous TNF-α (20 ng/mL) decreased <it>HJV</it> mRNA and protein expression to 40% of control with no effect on <it>hepcidin</it> mRNA expression in 24 hours. On the other hand, IL-6 induced <it>hepcidin</it> mRNA and protein expression with no effect on <it>HJV</it> mRNA expression levels. Moreover, using the <it>HJV</it> promoter-luciferase reporter fusion construct <it>(HJVP1.2-luc)</it>, we showed that the basal luciferase activity of <it>HJVP1.2-luc</it> was inhibited by 33% following TNF-α treatment of HuH7 transfected cells suggesting that the TNF-α down-regulation is exerted at the transcriptional level. Additionally, mutation of a canonical TNF- alpha responsive element (TNFRE) within <it>HJVP1.2-luc</it> abolished TNF-α response suggesting that this TNFRE is functional.</p> <p>Conclusions</p> <p>From these results, we conclude that TNF-α suppresses <it>HJV</it> transcription possibly via a novel TNFRE within the <it>HJV</it> promoter. In addition, the results suggest that the proposed link between inflammation and BMP-SMAD signalling is independent of HJV and BMP ligands.</p> |
|---|---|
| ISSN: | 1021-7770 1423-0127 |