title: Bacterial cell wall constituents induce hepcidin expression in macrophages through MyD88 signaling.
abstract: Hepcidin is a key regulator of iron recycling by macrophages that is synthesized mainly by hepatocytes but also by macrophages. However, very little is known about the molecular regulation of hepcidin in macrophages. In the present study, we investigated hepcidin regulation in the RAW264.7 macrophage cell line and in murine peritoneal macrophages stimulated with different Toll-like receptor (TLR) ligands. We found that TLR-2 and TLR-4 ligands activated hepcidin expression in RAW264.7 cells and in wild-type murine peritoneal macrophages, but not in murine peritoneal macrophages isolated from TLR2(-/-), TLR-4-deficient or MyD88(-/-) mice. IL-6 production by RAW264.7 cells stimulated with lipopolysaccharide (LPS, TLR4 ligand) was enhanced by high amounts of iron present in the culture medium. We conclude that hepcidin expression in macrophages is regulated mainly through TLR2 and TLR4 receptors via the MyD88-dependent signaling pathway and that autocrine regulation of iron accumulation in macrophages by hepcidin may affect the levels of proinflammatory cytokine production.
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Hôpital Notre-Dame, Pav. De Sève Y5625, 1560 rue Sherbrooke est, Montréal, Québec, H2L 4M1, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Layoun
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D002460:Cell Line; D002473:Cell Wall / Q000378:metabolism*; D003470:Culture Media; D005260:Female; D064451:Hepcidins; D015850:Interleukin-6 / Q000096:biosynthesis; D007501:Iron / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D003470:Culture Media; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D007501:Iron