Suppression of TNF-alpha gene expression by hemin: implications for the role of iron homeostasis in host inflammatory responses.
Tumor necrosis factor alpha (TNF-alpha) has multiple effects on iron homeostasis and erythropoiesis and has been implicated in the pathogenesis of the anemia of inflammation. We postulated that intracellular iron in turn may regulate the expression of TNF-alpha. In the human monocytic leukemia cell line, THP-1, low basal TNF-alpha message levels were stimulated (sevenfold) when serum was excluded from the culture medium. Addition of hemin completely suppressed TNF-alpha expression. Similarly, hemin suppressed lipopolysaccharide-induced expression of TNF-alpha. Sn-protoporphyrin, an inhibitor of heme oxygenase (which releases iron from hemin), prevented hemin-induced suppression of TNF-alpha expression. Conversely, the intracellular iron chelator, desferrioxamine, stimulated TNF-alpha expression. Thus, the expression of TNF-alpha, itself a physiological regulator of iron homeostasis, appears to be controlled by intracellular levels of iron.
Silver
B J
BJ
Division of Hematology/Oncology, Veterans Administration Medical Center and Case Western Reserve University, Cleveland, Ohio 44106, USA.
Hamilton
B D
BD
Toossi
Z
Z
D001769:Blood; D003470:Culture Media; D003676:Deferoxamine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006427:Hemin / Q000494:pharmacology*; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D007501:Iron / Q000378:metabolism*; D058085:Iron Compounds / Q000494:pharmacology; D007948:Leukemia, Monocytic, Acute; D008070:Lipopolysaccharides / Q000494:pharmacology; D011166:Porphyrins / Q000494:pharmacology; D013489:Suppression, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D003470:Culture Media; D058085:Iron Compounds; D008070:Lipopolysaccharides; D011166:Porphyrins; D014409:Tumor Necrosis Factor-alpha; D006427:Hemin; D007501:Iron; D003676:Deferoxamine