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 h omeostasis and erythropoiesis and has been implicated in the pathogene sis of the anemia of inflammation. We postulated that intracellular ir on in turn may regulate the expression of TNF-alpha, In the human mono cytic leukemia cell line, THP-1, low basal TNF-alpha message levels we re stimulated (sevenfold) when serum was excluded from the culture med ium, Addition of hemin completely suppressed TNF-alpha expression, Sim ilarly, hemin suppressed lipopolysaccharide-induced expression of TNF- alpha. Sn-protoporphyrin, an inhibitor of heme oxygenase (which releas es iron from hemin), prevented hemin-induced suppression of TNF-alpha expression, Conversely, the intracellular iron chelator, desferrioxami ne, 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.