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Activin B Induces Noncanonical SMAD1/5/8 Signaling via BMP Type I Receptors in Hepatocytes: Evidence for a Role in Hepcidin Induction by Inflammation in Male Mice
| Content Provider | Paperity |
|---|---|
| Author | Babitt, Jodie L. Pietrangelo, Antonello Canali, Susanna Zumbrennen-Bullough, Kimberly B. Core, Amanda B. Merkulova, Maria Wang, Chia-Yu Schneyer, Alan L. |
| Abstract | Induction of the iron regulatory hormone hepcidin contributes to the anemia of inflammation. Bone morphogenetic protein 6 (BMP6) signaling is a central regulator of hepcidin expression in the liver. Recently, the TGF-β/BMP superfamily member activin B was implicated in hepcidin induction by inflammation via noncanonical SMAD1/5/8 signaling, but its mechanism of action and functional significance in vivo remain uncertain. Here, we show that low concentrations of activin B, but not activin A, stimulate prolonged SMAD1/5/8 signaling and hepcidin expression in liver cells to a similar degree as canonical SMAD2/3 signaling, and with similar or modestly reduced potency compared with BMP6. Activin B stimulates hepcidin via classical activin type II receptors ACVR2A and ACVR2B, noncanonical BMP type I receptors activin receptor-like kinase 2 and activin receptor-like kinase 3, and SMAD5. The coreceptor hemojuvelin binds to activin B and facilitates activin B-SMAD1/5/8 signaling. Activin B-SMAD1/5/8 signaling has some selectivity for hepatocyte-derived cells and is not enabled by hemojuvelin in other cell types. Liver activin B mRNA expression is up-regulated in multiple mouse models of inflammation associated with increased hepcidin and hypoferremia, including lipopolysaccharide, turpentine, and heat-killed Brucella abortus models. Finally, the activin inhibitor follistatin-315 blunts hepcidin induction by lipopolysaccharide or B. abortus in mice. Our data elucidate a novel mechanism for noncanonical SMAD activation and support a likely functional role for activin B in hepcidin stimulation during inflammation in vivo. |
| Starting Page | 1146 |
| Ending Page | 1162 |
| File Format | HTM / HTML |
| ISSN | 00137227 |
| DOI | 10.1210/en.2015-1747 |
| Issue Number | 3 |
| Journal | Endocrinology |
| Volume Number | 157 |
| e-ISSN | 19457170 |
| Language | English |
| Publisher | Oxford University Press |
| Publisher Date | 2016-03-01 |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
| Subject | Endocrinology |
