Abstract
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).
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References
Caughman, S.W., Hentze, M.W., Rouault, T.A., Harford, J.B. and Klausner R.D., 1988, The iron responsive element is the single element responsible for iron-dependent translational regulation of ferritin biosynthesis, J.Biol. Chem. 263: 19048.
Cox, T.C., Bawden, M.J., Martin, A. and May, B.K., 1991, Human erythroid 5-aminolevulinate synthase: promoter analysis and identification pf an iron-responsive element in the mRNA, EMBO J. 10: 1891.
Dandekar, T., Stripecke, R, Gray, N., Goossen, B., Constable, A., Johansson, H.E. and Hentze, M.W., 1991, Identification of a novel iron-responsive element in murine and erythroid 5-aminolevulinic acid synthase mRNA, EMBO J. 10: 1903.
Drapier, J.C., and Hibbs, J.B., 1986, Murine cytotoxic activated macrophages inhibit aconitase in tumor cells, J.Clin. Invest. 78: 790.
Drapier, J.C., and Hibbs, J.B., 1988, Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells result in L-arginine dependent inhibition of mitochondrial iron sulfur enzymes in the macrophage effector cells, J. Immunol., 140: 2829.
Fuchs, D., Hausen, A, Reibnegger, G., Werner, E.R, Werner-Felmayer, G., Dierich, M.P. and Wachter, H., 1991, Immune activation and the anaemia associated with chronic inflammatory disorders, Eur. J. Haematol. 46: 65.
Fuchs, D., Zangerle, R, Artner-Dworzak, E., Weiss, G., Fritsch, P., Tilz, G.P., Dierich, M.P. and Wachter, H., 1993, Association between immune activation, chances of iron metabolism and anaemia in patients with HIV infection, Eur J. Haematol. 50: 90.
Haile, D.J., Rouault, T.A., Tang, C.K., Chin, J., Harford, J.B. and Klausner, R.D., 1992, Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron responsive element binding protein: role of the iron sulfur cluster, Proc. Nartl. Acad. Sci. USA 89: 7536.
Hentze, M.W., Caughman, S.W., Rouault, T.A., Barriocanal, J.G., Dancis, A., Harford, J.B., and Klausner, R.D., 1987, Identification of the iron responsive element for the regulation of human ferritin mRNA, Science 238: 1570.
Hentze, M.W., Caughman, S.W., Casey, J.L., Rouault, T.A, Harford, J.B., and Klausner, R.D., 1988, A model for structure and function of iron-responsive elements, Gene 72: 201.
Hentze, M.W., Rouault, T.A., Harford, J.B. and Klausner, R.D., 1989, Oxidationreduction and the molecular mechanism of a regulated RNA-protein interaction, Science, 244: 357.
Hentze, M.W. and Argos, P., 1991, Homology between IRE-BP, a regulatory RNA-binding protein, aconitase and isopropylmalate isomerase, Nucl. Acids Res. 19: 1739.
Huber, C., Batchelor, J.R., Fuchs, D., Hausen, A., Lang, A., Neiderwieser, D., Reibnegger, G., Swetly, P., Troppmair, J. and Wachter, H., 1984, Immune resonse associated production of neopterin, J. Exp. Med. 160: 310.
Kaufman, S., 1963, The structure of the phenylalanine hydroxylation cofactor, Proc. Natl. Acad. Sci. USA 50: 1085.
Klausner, R, Rouault, T.A. and Harford, J.B., 1993, Regulating the fate of mRNA: The control of cellular iron metabolism, Cell 72: 19.
Kwon, N.S., Nathan, C.F., and Stuehr, D.J., 1989, Reduced biopterin as a cofactor in the generation of nitric oxides by murine macrophages, J. Biol. Chem. 264: 20496.
Leibold, E.A. and Munro, H.N., 1988, Cytoplasmatic protein binds in vitro to a highly conserved sequence in the 5’ untranslated regions of ferritin heavy-and light subunit mRNAs, Proc. Natl. Acad. Sci. USA 85: 2171.
Means, R.T. and Krantz, S.B., 1992, Progress in understanding the pathogenesis of anemia of chronic disease, Blood 80: 1639.
Melfors, OÖ., Goossen, B., Johansson, H.E., Stripecke, R., Gray, N.K. and Hentze, M.W., 1993, Translational control of 5-aminolevulinate synthase mRNA by iron responsive elements in erythroid cells, J. Biol. Chem. 268: 5974.
Milligan, J.F., Groebe, D.R., Witherell, G.W., and Uhlenbeck, O.C., 1987, Oligoribonucleotide synthesis using T7 RNA polymerase and synthetic DNA templates, Nucl. Acids Res. 15: 8783.
Müllner, E.W: and Kühn, L.C., 1988, A stem-loop in the 3’ untranslated region mediates iron dependent regulation of transferrin receptor mRNA stability in the cytoplasm, Cell, 58: 372.
Müllner, E.W., Neupert, B. and Kühn, L.C., 1989, A specific mRNA binding factor regulates the iron-dependent stability of cytoplasmatic transferrin receptor mRNA, Cell 58: 373.
Nichol, C.A., Smith, G.K., and Duch D.S., 1985, Biosynthesis and metabolism of tetrahydrobiopterin and molybdopterin, Ann. Rev. Biochem. 54: 729.
Rouault, T.A., Stout, C.D., Kaptain, S., Harford, J.B. and Klausner, R.D., 1991, Structural relationship between an iron-regulated RNA-binding protein (IRE-BP) and aconitase: Functional implications, Cell, 64: 881.
Stamatatos, L., Leventis, R., Zuckermann, M.J. and Silvius, J.R., 1988, Interactions of cationic lipid vesicles with negatively charged phospholipid vesicles and biological membranes, Biochemistry 27, 3917.
Tayeh, M.A., and Marietta, M.A., 1989, Macrophage oxidation of L-arginine to nitric oxide, nitrite and nitrate, J. Biol. Chem. 264: 19654.
Weinberg, E.D., 1984, Iron withholding. A defense against infection and neoplasia, Physiol. Rev. 64: 65.
Weiss, G., Fuchs, D., Hausen, A., Reibnegger, G, Werner, E.R., Werner-Felmayer, G., and Wachter H, 1992, Iron modulates interferon-gamma effects in human myelomonocytic cell line THP-1, Exp. Hematol. 20: 605.
Weiss, G., Lutton, J.D., Fuchs, D., Werner-Felmayer, G, Böck, G, Abraham, N.G, Kappas, A., Levere, R.D., and Wachter H., 1993a, Comparative effects of heme and metalloporphyrins on interferon-gamma mediated pathways in monocytic cells, Proc. Soc. Exp. Biol. Med. 202: 470.
Weiss, G., Goossen, B., Doppler, W., Fuchs, D., Pantopoulos, K., Werner-Felmayer, G., Wachter, H. and Hentze, M.W. 1993b, Translational regulation via iron responsive elements by the nitric oxide/NO-synthase pathway. EMBO J., 12: 3651.
Werner, E.R., Werner-Felmayer, G., Fuchs, D., Hausen A., Reibnegger, G, Yim, J.J., Pfleiderer, W., and Wachter, H., 1990, Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP-1 and T-24 cells, J. Biol. Chem. 265: 3189.
Werner-Felmayer, G., Werner, E.R., Fuchs, D., Hausen, A., Reibnegger, G., and Wachter, H., 1990, Tetrahydrobiopterin dependent formation of nitrite and nitrate in murine fibroblasts, J. Exp. Med. 172: 1599.
Werner-Felmayer, G., Werner, E.R., Fuchs, D., Hausen, A., Reibnegger, G., Schmidt, K., Weiss, G. and Wachter, H., 1993a, Pteridine biosynthesis in human endothelial cells, J. Biol. Chem. 268: 1842.
Werner-Felmayer, G., Werner, E.R., Fuchs, D., Hausen, A., Mayer, B., Reibnegger, G., Weiss, G. and Wachter, H., 1993b, Ca+2/calmodulin dependent nitric oxide synthase activity in human cervix carcinoma cell line Me-180, Biochem. J. 289: 357.
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Weiss, G. et al. (1994). Stimulation of IRE-BP Activity of IRF by Tetrahydrobiopterin and Cytokine Dependent Induction of Nitric Oxide Synthase. In: Hershko, C., Konijn, A.M., Aisen, P. (eds) Progress in Iron Research. Advances in Experimental Medicine and Biology, vol 356. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2554-7_15
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DOI: https://doi.org/10.1007/978-1-4615-2554-7_15
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