Abstract
Anemia is one of the most common complications in patients with inflammatory bowel disease (IBD). Hepcidin as a key regulator of iron metabolism is pivotal in mediating the occurrence of anemia of chronic disease. Herein, we analyzed the levels of hepcidin in sera from IBD patients by enzyme-linked immunosorbent assay and investigated its potential role in regulating the anemia in IBD. We observed that the levels of serum hepcidin were increased in active IBD patients compared with those in remitted IBD patients and healthy controls and that serum hepcidin was associated with disease activity, CRP, and ESR, respectively. Importantly, we found that the increased levels of serum hepcidin were positively correlated with the severity of anemia and the imbalance of iron metabolism in anemic UC and CD patients. Proinflammatory factors (e.g., IL-6, IL-17, and TNF-α) were positively correlated with the concentrations of serum hepcidin in IBD patients. Interestingly, hepcidin was found to be decreased in patients with Crohn's disease after successful therapy with anti-TNF-α mAb (i.e., infliximab), indicating the underlying association between TNF-α and hepcidin expression. To investigate the specific mechanisms involved, we cultured LO2 and HepG2 cell lines in vitro under stimulation with TNF-α and observed that the levels of hepcidin mRNA were markedly upregulated in caspase-3/8- and NF-κB-dependent manners. Therefore, our data suggest that TNF-α stimulates the expression of hepcidin in IBD patients, resulting in aggravated anemia and that blockage of TNF-α or the caspase-3/8 and NF-κB pathways could downregulate hepcidin expression. This study provides inspiration for the therapy and management of anemia in IBD.
Highlights
Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases caused by dysregulated immune response to microbiota in the gastrointestinal tract and consists of two major forms, including Crohn’s disease (CD) and ulcerative colitis (UC)
We investigated hepcidin expression in the sera of IBD patients and found that the concentrations of hepcidin were higher in the sera of active IBD patients than in remitted IBD patients and healthy controls
To further investigate the clinical relevance of anemia to the pathogenesis of IBD, we focused on hepcidin which plays a pivotal role in regulating iron metabolism
Summary
Inflammatory bowel disease (IBD) is a group of chronic inflammatory diseases caused by dysregulated immune response to microbiota in the gastrointestinal tract and consists of two major forms, including Crohn’s disease (CD) and ulcerative colitis (UC). A cysteine-rich and antimicrobial peptide, is mainly synthesized and secreted by the liver. It consists of 8 cysteine residues, forming a single hairpin structure which contains 4 two-sulfur bonds, and its amino acid sequence is highly conserved among different mammals [10, 11]. Hepcidin is responsible for the regulation of the iron homeostasis in the human body and other mammals by binding and downregulating ferroportin (FPN), the only known iron exporter that promotes iron absorption by duodenal enterocytes and pumps iron out of phagocytes and hepatocytes [14,15,16]. The hepcidin-FPN axis is considered as the central player in regulating iron homeostasis [17]
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