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/BMPsuperfamily 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 SMAD2β 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 receptorlike 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.

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 / Canali, Susanna; Core, Amanda B.; Zumbrennen Bullough, Kimberly B.; Merkulova, Maria; Wang, Chia Yu; Schneyer, Alan L.; Pietrangelo, Antonello; Babitt, Jodie L.. - In: ENDOCRINOLOGY. - ISSN 0013-7227. - 157:3(2016), pp. 1146-1162. [10.1210/en.2015-1747]

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

CANALI, SUSANNA;PIETRANGELO, Antonello;
2016

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/BMPsuperfamily 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 SMAD2β 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 receptorlike 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.
6-gen-2016
157
3
1146
1162
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 / Canali, Susanna; Core, Amanda B.; Zumbrennen Bullough, Kimberly B.; Merkulova, Maria; Wang, Chia Yu; Schneyer, Alan L.; Pietrangelo, Antonello; Babitt, Jodie L.. - In: ENDOCRINOLOGY. - ISSN 0013-7227. - 157:3(2016), pp. 1146-1162. [10.1210/en.2015-1747]
Canali, Susanna; Core, Amanda B.; Zumbrennen Bullough, Kimberly B.; Merkulova, Maria; Wang, Chia Yu; Schneyer, Alan L.; Pietrangelo, Antonello; Babitt, Jodie L.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1107416
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