Regulation of hepcidin and ferroportin expression by lipopolysaccharide in splenic macrophages.
Acute and chronic inflammatory states are associated with many changes in intracellular iron metabolism including sequestration of iron in the mononuclear-phagocyte system (MPS) and a decline in serum iron. Previous work in rodent models of acute inflammation has demonstrated inflammation-induced downregulation of intestinal and MPS iron exporter, ferroportin 1, mRNA and protein. In addition, these models have also demonstrated hepatic induction of mRNA of the small 25 amino acid peptide hepcidin. Hepcidin has been hypothesized to be the mediator of iron- and inflammation-induced changes in iron metabolism. The molecular details of the connection between iron metabolism, hepcidin and inflammation have become clearer with the recent finding of hepcidin-induced internalization and degradation of FPN1. The work presented here demonstrates that the lipopolysaccharide-induced splenic macrophage FPN1 mRNA downregulation is not dependent upon the action of a single cytokine such as IL-6, IL-1 or TNF-alpha because mice deficient in these pathways downregulate FPN1 normally. Furthermore, hepcidin is also synthesized in the spleen of normal mice and induced by lipopolysaccharide. Additionally, in vitro, splenic adherent cells produce hepcidin in response to lipopolysaccharide in an IL-6-dependent manner. There appear to be both probable transcriptional and post-transcriptional control of FPN1 expression by lipopolysaccharide-induced inflammation. The former effect is on mRNA expression and is independent of hepcidin, whereas the latter is IL-6- and hepcidin-dependent.
Liu
Xiao-Bing
XB
Audie Murphy Veterans Administration Hospital, South Texas Veterans Health Care System, San Antonio, San Antonio, TX 78229, USA.
Nguyen
Ngoc-Bich H
NB
Marquess
Kimberly D
KD
Yang
Funmei
F
Haile
David J
DJ
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000187:drug effects*; D064451:Hepcidins; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000032:analysis; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D000098742:Ferroportin
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000098742:Ferroportin; D007501:Iron