Stimulation of IRE-BP Activity of IRF by Tetrahydrobiopterin and Cytokine Dependent Induction of Nitric Oxide Synthase
Hypoferric anemia is very frequent in patients suffering from chronic inflammatory disorders or malignancies. This type of anemia is characterized by decreased amounts of serum iron and hemoglobin but increased body iron stores reflected by an increase of ferritin concentrations as well as by enhanced amounts of cellular immune activation markers like interferon-gamma and pteridines (Weinberg, 1984; Fuchs et al., 1991 and 1993; Means and Krantz, 1992). It was shown recently that increased intracellular concentrations of low molecular weight iron inhibit the efficiency of the interferon-gamma signal in human monocytic cells as checked by decreased cytokine induced MHC class II antigen expression, tryptophan degaradtion or pteridine formation in the presence of iron (Weiss et al., 1992 and 1993a). Pteridines are pyrazino-pyrimidino compounds which are synthezised in excess by human monocytes/macrophages upon stimualtion with cytokines such as interferon-gamma (Huber et al., 1984). Starting from GTP the first intermediate of the biosynthetic pathway, i.e. 7,8-dihydroneopterintriphosphate, is either converted by two subsequent enzymes to 5,6,7,8-tetrahydrobiopterin known to be an essential cofactor for hydroxylation reacrtions or nitric oxide synthase (Kaufmann, 1963; Tayeh and Marietta 1989; Kwon et al., 1989), or cleaved by omnipresent phosphatases to form 7,8-dihydroneopterin (Nichol et al., 1986; Werner et al., 1990).
KeywordsNitric Oxide K562 Cell Iron Metabolism Chronic Inflammatory Disorder Iron Responsive Element
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