Up-regulation of hepcidin by interleukin-6 contributes to anemia of inflammation in multicentric Castleman's disease (MCD)

Abstract

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder characterized by overproduction of interleukin-6 (IL-6). Anemia is a common symptom of MCD but its mechanism has been poorly understood. Hepcidin is an IL-6-induced key regulator of iron metabolism and has a major role in anemia of inflammation (AI). Our study showed that treatment with tocilizumab (an anti-IL-6 receptor antibody) resulted in long-term reductions of serum hepcidin25 in MCD patients, which was accompanied by progressive normalization of iron-related parameters. In in vitro experiments, IL-6-induced hepcidin mRNA expression in hepatocytes was completely inhibited with tocilizumab and partially with erythropoietin (EPO), but enhanced by bone morphogenetic protein (BMP) and patient's serum. Our findings and evidence published elsewhere, leads us to suggest that, although multiple factors affect hepcidin levels, IL-6 plays an essential role in the induction of hepcidin which leads to anemia in MCD. Therefore, IL-6 blockage may constitute a promising molecular targeting therapy for AI.