Dysregulated production of hepcidin is implicated in anemia of inflammation, and IL-6 is a major inducer of hepcidin production. Increased inflammatory cytokines, especially IL-6, are responsible for the pathogenesis of MCD and rheumatoid arthritis. At a study presented at ASH 2014, Yoshizaki and colleagues studied the role of hepcidin and IL-6 in patients with anemia of inflammation and MCD or rheumatoid arthritis by investigating the effect of tocilizumab, an anti–IL-6 receptor antibody, on serum hepcidin and the relationship between hepcidin and iron-related parameters (Yoshizaki K, et al. Blood. 2014;124. Abstract 4006).
The mechanism involving inflammatory anemia in patients with MCD and rheumatoid arthritis was further analyzed in vitro by studying 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.
The data showed that treatment with tocilizumab resulted in a rapid reduction of serum hepcidin-25 in patients with MCD and rheumatoid arthritis. Furthermore, long-term reductions (>1 year) of hepcidin-25 were observed in 10 cases of MCD after treatment with tocilizumab, accompanied by progressive normalization of iron-related parameters and improved disease activity. In in vitro experiments, IL-6, but not tumor necrosis factor-? or IL-1, induced the upregulation of hepcidin mRNA in hepatoma cell lines that was completely inhibited with tocilizumab, but enhanced by BMP4 and the serum from a patient with MCD.
These results suggest that, although multiple factors affect serum hepcidin levels, IL-6 plays an essential role in the induction of hepcidin; thus, the long-term ameliorative effect of IL-6 blockade with tocilizumab on anemia is through the inhibition of hepcidin production in patients with MCD and rheumatoid arthritis.
