Tumor Necrosis Factor \(\alpha\) Inhibits Expression of the Iron Regulating Hormone Hepcidin in Murine Models of Innate Colitis
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CitationShanmugam, Nanda Kumar N., Shiri Ellenbogen, Estela Trebicka, Lijian Wang, Subhankar Mukhopadhyay, Adam Lacy-Hulbert, Carey Ann Gallini, Wendy S. Garrett, and Bobby J. Cherayil. 2012. Tumor necrosis factor \(\alpha\) inhibits expression of the iron regulating hormone hepcidin in murine models of innate colitis. PLoS ONE 7(5).
AbstractBackground: Abnormal expression of the liver peptide hormone hepcidin, a key regulator of iron homeostasis, contributes to the pathogenesis of anemia in conditions such as inflammatory bowel disease (IBD). Since little is known about the mechanisms that control hepcidin expression during states of intestinal inflammation, we sought to shed light on this issue using mouse models. Methodology/Principal Findings: Hepcidin expression was evaluated in two types of intestinal inflammation caused by innate immune activation—dextran sulfate sodium (DSS)-induced colitis in wild-type mice and the spontaneous colitis occurring in T-bet/Rag2-deficient (TRUC) mice. The role of tumor necrosis factor (TNF) \(\alpha\) was investigated by in vivo neutralization, and by treatment of a hepatocyte cell line, as well as mice, with the recombinant cytokine. Expression and activation of Smad1, a positive regulator of hepcidin transcription, were assessed during colitis and following administration or neutralization of TNF\(\alpha\). Hepcidin expression progressively decreased with time during DSS colitis, correlating with changes in systemic iron distribution. TNF\(\alpha\) inhibited hepcidin expression in cultured hepatocytes and non-colitic mice, while TNF\(\alpha\) neutralization during DSS colitis increased it. Similar results were obtained in TRUC mice. These effects involved a TNF\(\alpha\)-dependent decrease in Smad1 protein but not mRNA. Conclusions/Significance: TNF\(\alpha\) inhibits hepcidin expression in two distinct types of innate colitis, with down-regulation of Smad1 protein playing an important role in this process. This inhibitory effect of TNF\(\alpha\) may be superseded by other factors in the context of T cell-mediated colitis given that in the latter form of intestinal inflammation hepcidin is usually up-regulated.
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