HEMIN INHIBITS THE INTERFERON-BETA-INDUCED ANTIVIRAL STATE IN ESTABLISHED CELL-LINES

Hemin and other metalloporphyrins are known as very versatile compounds in nature, because they are able to carry out numerous functions in a free state or in association with specific proteins. When Friend murine erythroleukemia cells are treated with IFN-beta plus 100 mu M hemin, the antiviral state is not observed, whereas the antiviral effect of IFN-gamma is unaffected by hemin treatment. This inhibitory effect of hemin is not restricted to erythroid cells. In fact, it is also observed in murine L929 and in human cell lines treated with IFN-beta. Neither trivalent iron in other forms nor hemin analogs (such as protoporphyrin IX or Sn2+-protoporphyrine IX) mimic this effect. Conversely, Co3+-protoporphyrin IX was as effective as hemin. At the transcriptional level, results obtained by run-on assays on nuclei from IFN-treated cells indicate that hemin does not completely inhibit IFN-beta induction of 2-5A synthetase gene(s) at 6 h of treatment but abolishes it at 24 h. In addition, hemin is able to inhibit the accumulation of IFN-induced 2-5A synthetase mRNAs. Experiments carried out to investigate the hemin effect on the early steps of the IFN signaling pathway indicate that hemin interferes with the ability of type I IFN to bind to its receptor, probably by a direct action on the IFN molecule.