Suppressing Hepcidin By Tocilizumab Effectively Improve Anemia in Inflammatory Diseases: Clinical Evidence and Basic Mechanisms

Abstract

IntroductionDysregulated production of hepcidin is implicated in anemia of inflammation (AI) and interleukin-6 (IL-6) is a major inducer of hepcidin production. Increased imflammatory cytokines, especially IL-6 is response for pathogenesis of multicentric Castleman’s disease (MCD) and rheumatoid arthritis (RA).Patients and MethodIn this study we study role of hepcidin and IL-6 in AI patients with MCD or RA, by investigating the effect of tocilizumab, an anti-IL-6 receptor antibody, on the serum hepcidin and relationship between hepcidin and iron-related parameters. The mechanism involving inflammatory anemia in MCD and RA was further analyzed in vitro by studied the transcriptional regulation of hepcidin in hepatoma-derived cell lines in the presence of cytokines, antibodies against cytokines, inhibitors of signal pathways and other hematopoietic factors.ResultsOur data showed that treatment with tocilizumab resulted in a rapid reduction of serum hepcidin-25 in MCD and RA patients. Although treatment with anti-TNF-a antibody also resulted in decrease of serum hepcidin, compared to tocilizumab therapy it decrease by a smaller margin. Furthermore, long-term reductions of hepcidin-25 were observed in ten MCD cases for one year after the start of tocilizumab treatment, which was accompanied by progressive normalization of iron-related parameters and improved disease activity. In in vitro experiments, IL-6, but not TNF-a or IL-1,-induced upregulation of hepcidin mRNA in hepatoma cell lines was completely inhibited with tocilizumab, and partially by EPO as well as TNF-a, but enhanced by BMP4 and MCD patient’s serum.DiscussionOur results suggest that, although multiple factors affect serum hepcidin levels, IL-6 plays an essential role in the induction of hepcidin. This accounts for the long-term ameliorative effect of IL-6 blockage with tocilizumab on anemia by inhibiting hepcidin production in MCD and RA patients. DisclosuresNo relevant conflicts of interest to declare.