Analysis of mechanism of different responses of acute-phase proteins to IL-6 and TNFα in chronic inflammatory diseases

抄録

Increase of acute-phase proteins in serum comprises a major pathophysiologic phenomenon during inflammatory states. Clinical studies revealed that serum level of SAA and CRP were normalized by ant-IL-6R Ab treatment, but not by anti-TNFα Ab in RA patients. By analyzing transcriptional mechanism in vitro, we found that IL-6-STAT3 signaling is essential for CRP/SAA induction and augmentation in the presence of TNFα. In addition, hepatic iron-regulated peptide hepcidin is an acute-phase reactant and its overexpression is response for anemia of inflammation (AI), and IL-6 is indicated as major inducer of hepcidin expression. We further found that anti-IL-6R Ab treatment resulted in reduction of serum hepcidin which accompanied by progressive normalization of iron-related parameters in MCD or RA patients in the present study. Although TNFα blockade also resulted in decrease of serum hepcidin in RA, it decreased by a smaller margin. In in vitro experiments, IL-6, but not TNFα induced hepcidin mRNA expression in hepatocytes was completely inhibited by anti-IL-6R Ab, and partially by EPO, but not by TNFa inhibitors. Our results suggest that IL-6-induced hepcidin plays a key role in the development of AI, TNFα may contribute to AI by hepcidin-independent mechanism.