Published online before print August 3, 2009

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(Journal of Leukocyte Biology. 2009;86:1247-1258.)
© 2009 Society for Leukocyte Biology

Role of STAT1, NF-B, and C/EBPβ in the macrophage transcriptional regulation of hepcidin by mycobacterial infection and IFN-

Fatoumata B. Sow^*,, Gail R. Alvarez^,, Ryan P. Gross^*,, Abhay R. Satoskar^*,, Larry S. Schlesinger^*,,,, Bruce S. Zwilling^*, and William P. Lafuse^,,1

Departments of
^* Microbiology,
Molecular Virology, Immunology, and Medical Genetics, and
Internal Medicine and
Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA

1. Correspondence: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, 333 W 10th Ave., Columbus, OH 43210, USA. E-mail: lafuse.1{at}osu.edu

ABSTRACT

Hepcidin is an antimicrobial peptide involved in regulating iron homeostasis. It is induced by iron overload and decreased by hypoxia and anemia. Hepcidin regulates iron metabolism by inhibiting iron absorption by the duodenum and by inhibiting macrophage iron recycling. Hepcidin is induced in hepatocytes during the acute-phase response by IL-6. Previously, we have shown that hepcidin is not induced in macrophages by IL-6 but is induced by the synergistic interaction of IFN- and Mycobacterium tuberculosis infection. In the present study, we examined the pathways involved in inducing macrophage hepcidin expression. We show that TLRs TLR2 and TLR4 and the transcription factor STAT1 are required for induction of hepcidin mRNA. Hepcidin promoter activity is also synergistically induced in RAW264.7 macrophages by IFN- and M. tuberculosis. NF-B and C/CEBP binding sites are required for promoter activity. Binding of NF-B (p50/p65) to the NF-B site and STAT1 and C/EBPβ to the C/CEBP site was confirmed by EMSA. Knockdown of STAT1 and C/EBPβ expression in RAW264.7 cells with siRNA plasmids inhibited hepcidin promoter activity induced by IFN- and M. tuberculosis. Together, these studies demonstrate that macrophage hepcidin expression is induced by the activation of STAT1 and NF-B and the induction of C/EBPβ expression.

Key Words: iron • Mycobacterium tuberculosis • interferon-