Induction of activin B by inflammatory stimuli up-regulates expression of the iron-regulatory peptide hepcidin through Smad1/5/8 signaling

Abstract

Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation. There is a dramatic induction of Inhbb mRNA, encoding the activin ␤ B -subunit, in the livers of mice challenged with lipopolysaccharide, slightly preceding an increase in Smad1/5/8 phosphorylation and Hamp mRNA. Activin B also induces Smad1/5/8 phosphorylation in human hepatoma-derived cells and, synergistically with IL-6 and STAT-3 signaling, upregulates hepcidin expression markedly, an observation confirmed in mouse primary hepatocytes. Pretreatment with a bone morphogenic protein type I receptor inhibitor showed that the effect of activin B on hepcidin expression is entirely attributable to its effect on bone morphogenetic protein signaling, most likely via activin receptor-like kinase 3. Activin B is therefore a novel and specific target for the treatment of anemia of inflammation. (Blood. 2012;120(2):431-439) IntroductionAnemia of inflammation develops as a complication of an acute or chronic activation of the immune response. It is particularly common in hospitalized patients and in the elderly and has a negative impact on recovery and survival. 1,2 Most chronic bacterial, fungal, viral, or parasitic infections with systemic manifestations can cause anemia of inflammation, as do rheumatologic disorders, systemic autoimmune disorders, inflammatory bowel disease, chronic kidney diseases, and some malignancies. 3 The limitation of iron supply to erythropoiesis is a major factor in the development of this anemia. Treatment includes administration of erythropoiesis-stimulating agents and intravenous iron. However, iron is rapidly trapped in the macrophage compartment, 4,5 rendering it unavailable for erythropoiesis once the initial iron bolus is incorporated into RBCs and body stores.Anemia of inflammation appears to be caused, at least in part, by the induction of the iron-regulatory hormone hepcidin. [6][7][8] Hepcidin acts by binding to the sole known iron-export channel, ferroportin, which is found on duodenal enterocytes, macrophages, and hepatocytes, the cell types that export iron into plasma. Binding of hepcidin to ferroportin induces its internalization and degradation, 9 which progressively inhibit iron efflux from these cells, leading to hypoferremia. The fundamental mechanisms causing increased hepcidin production by the liver during inflammation are still incompletely understood, but a cross-talk with the pathway through which hepcidin is regulated by iron is not excluded.Iron overload induces the expression of bone morphogenetic protein 6 (BMP6), a member of the TGF-␤ superfamily. Binding of BMP6 to paired serine/thr...

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

“…Furthermore, activin B, a member of the TGF-␤ superfamily, is involved in response to inflammation in an IL-6-independent manner (52). Upon treatment with LPS, expression of the activin ␤ (B)-subunit is significantly increased, and this leads to a rise in SMAD1/5/8 phosphorylation and subsequent hepcidin induction.…”

Manipulation of the hepcidin pathway for therapeutic purposes

“…32 Other cytokines that activate the STAT pathway can also increase hepcidin transcription, including IL-22 and oncostatin M. 33,34 The BMP pathway synergistically stimulates hepcidin expression during inflammation. 33,35 Additionally, activin B, a member of the TGF-β superfamily, has been suggested to mediate hepcidin increase after LPS injection even in IL-6 knockout mice, 36 by activating the Smad1/5/8 pathway.…”

Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia

“…25 Thus, the role of IL-6 in hepcidin induction in malaria remains controversial. Notably, in comparison to mice injected with LPS, 40 we did not observe any physiologically relevant increase in serum IL-6 concentration 4 to 5 days after infection with PbK, and phosphorylated STAT3 was not detected in hepatocytes (Figure 4 and Online Supplementary Figure S1). Activin B is a ligand of the TGF-β superfamily that is upregulated by inflammatory…”

“…40 Similarly to IL-6, we detected only a mild induction of activin B mRNA expression compared to mice challenged with LPS ( Figure 4). It is therefore unlikely that IL-6 and activin B stimulate hepcidin expression during Plasmodium berghei infection.…”