Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 1991 Dec 15;280(Pt 3):709–714. doi: 10.1042/bj2800709

Impact of tumour necrosis factor-alpha and interferon-gamma on tetrahydrobiopterin synthesis in murine fibroblasts and macrophages.

E R Werner 1, G Werner-Felmayer 1, D Fuchs 1, A Hausen 1, G Reibnegger 1, J J Yim 1, H Wachter 1
PMCID: PMC1130511  PMID: 1764035

Abstract

Tumour necrosis factor-alpha causes an up to 30-fold induction of GTP cyclohydrolase I (EC 3.5.4.16) activity in murine dermal fibroblasts in a dose-dependent manner. Owing to the high constitutive activities of 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase (EC 1.1.1.153), this potentiates biosynthesis of tetrahydrobiopterin. Murine macrophages already contain high activities of GTP cyclohydrolase I when unstimulated, and this is further augmented up to 4-fold by tumour necrosis factor-alpha/interferon-gamma. In Western blots an antiserum to murine liver GTP cyclohydrolase I does not stain cell extracts with high enzyme activities, suggesting that the cytokine induced peripheral form of GTP cyclohydrolase I might differ from the liver form.

Full text

PDF
709

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  2. Cha K. W., Jacobson K. B., Yim J. J. Isolation and characterization of GTP cyclohydrolase I from mouse liver. Comparison of normal and the hph-1 mutant. J Biol Chem. 1991 Jul 5;266(19):12294–12300. [PubMed] [Google Scholar]
  3. Duch D. S., Bowers S. W., Woolf J. H., Nichol C. A. Biopterin cofactor biosynthesis: GTP cyclohydrolase, neopterin and biopterin in tissues and body fluids of mammalian species. Life Sci. 1984 Oct 29;35(18):1895–1901. doi: 10.1016/0024-3205(84)90541-1. [DOI] [PubMed] [Google Scholar]
  4. Faltynek C. R., McCandless S., Chebath J., Baglioni C. Different mechanisms for activation of gene transcription by interferons alpha and gamma. Virology. 1985 Jul 15;144(1):173–180. doi: 10.1016/0042-6822(85)90315-0. [DOI] [PubMed] [Google Scholar]
  5. Fukushima T., Nixon J. C. Analysis of reduced forms of biopterin in biological tissues and fluids. Anal Biochem. 1980 Feb;102(1):176–188. doi: 10.1016/0003-2697(80)90336-x. [DOI] [PubMed] [Google Scholar]
  6. Goldberg M., Gassner F., Merkenschlager M. Altered urinary excretion of pteridines in dogs with various tumours. Zentralbl Veterinarmed A. 1987 Aug;34(7):481–486. doi: 10.1111/j.1439-0442.1987.tb00308.x. [DOI] [PubMed] [Google Scholar]
  7. Huber C., Batchelor J. R., Fuchs D., Hausen A., Lang A., Niederwieser D., Reibnegger G., Swetly P., Troppmair J., Wachter H. Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma. J Exp Med. 1984 Jul 1;160(1):310–316. doi: 10.1084/jem.160.1.310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kaufman S., Pollock R. J., Summer G. K., Das A. K., Hajra A. K. Dependence of an alkyl glycol-ether monooxygenase activity upon tetrahydropterins. Biochim Biophys Acta. 1990 Aug 1;1040(1):19–27. doi: 10.1016/0167-4838(90)90141-2. [DOI] [PubMed] [Google Scholar]
  9. Kwon N. S., Nathan C. F., Stuehr D. J. Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J Biol Chem. 1989 Dec 5;264(34):20496–20501. [PubMed] [Google Scholar]
  10. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  11. Leary J. J., Brigati D. J., Ward D. C. Rapid and sensitive colorimetric method for visualizing biotin-labeled DNA probes hybridized to DNA or RNA immobilized on nitrocellulose: Bio-blots. Proc Natl Acad Sci U S A. 1983 Jul;80(13):4045–4049. doi: 10.1073/pnas.80.13.4045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Marletta M. A. Nitric oxide: biosynthesis and biological significance. Trends Biochem Sci. 1989 Dec;14(12):488–492. doi: 10.1016/0968-0004(89)90181-3. [DOI] [PubMed] [Google Scholar]
  13. Mura P., Morlier J. P., Barriere M., Bredon P., Papet Y., Chameaud J. Increased biopterin production in rats with tumors induced by radon inhalation and benzonaphthoflavone administration. Cancer Lett. 1990 Oct 8;54(1-2):57–60. doi: 10.1016/0304-3835(90)90091-b. [DOI] [PubMed] [Google Scholar]
  14. Nichol C. A., Smith G. K., Duch D. S. Biosynthesis and metabolism of tetrahydrobiopterin and molybdopterin. Annu Rev Biochem. 1985;54:729–764. doi: 10.1146/annurev.bi.54.070185.003501. [DOI] [PubMed] [Google Scholar]
  15. Osborn L., Kunkel S., Nabel G. J. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. doi: 10.1073/pnas.86.7.2336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Russell W. C., Newman C., Williamson D. H. A simple cytochemical technique for demonstration of DNA in cells infected with mycoplasmas and viruses. Nature. 1975 Feb 6;253(5491):461–462. doi: 10.1038/253461a0. [DOI] [PubMed] [Google Scholar]
  17. Schoedon G., Troppmair J., Adolf G., Huber C., Niederwieser A. Interferon-gamma enhances biosynthesis of pterins in peripheral blood mononuclear cells by induction of GTP-cyclohydrolase I activity. J Interferon Res. 1986 Dec;6(6):697–703. doi: 10.1089/jir.1986.6.697. [DOI] [PubMed] [Google Scholar]
  18. Schoedon G., Troppmair J., Fontana A., Huber C., Curtius H. C., Niederwieser A. Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse. Eur J Biochem. 1987 Jul 15;166(2):303–310. doi: 10.1111/j.1432-1033.1987.tb13515.x. [DOI] [PubMed] [Google Scholar]
  19. Sen R., Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell. 1986 Dec 26;47(6):921–928. doi: 10.1016/0092-8674(86)90807-x. [DOI] [PubMed] [Google Scholar]
  20. Tayeh M. A., Marletta M. A. Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. J Biol Chem. 1989 Nov 25;264(33):19654–19658. [PubMed] [Google Scholar]
  21. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wachter H., Fuchs D., Hausen A., Reibnegger G., Werner E. R. Neopterin as marker for activation of cellular immunity: immunologic basis and clinical application. Adv Clin Chem. 1989;27:81–141. doi: 10.1016/s0065-2423(08)60182-1. [DOI] [PubMed] [Google Scholar]
  23. Wachter H., Grassmayr K., Hausen A. Enhanced urinary excretion of 7,8-dihydro-6-hydroxylumazine by mice bearing the Ehrlich ascites tumour. Cancer Lett. 1979 Feb;6(2):61–66. doi: 10.1016/s0304-3835(79)80001-4. [DOI] [PubMed] [Google Scholar]
  24. Wachter H., Hausen A., Grassmayr K. Erhöhte Ausscheidung von Neopterin im Harn von Patienten mit malignen Tumoren und mit Viruserkrankungen. Hoppe Seylers Z Physiol Chem. 1979 Dec;360(12):1957–1960. [PubMed] [Google Scholar]
  25. Warren M. K., Vogel S. N. Bone marrow-derived macrophages: development and regulation of differentiation markers by colony-stimulating factor and interferons. J Immunol. 1985 Feb;134(2):982–989. [PubMed] [Google Scholar]
  26. Watanabe Y., Yoshida R., Sono M., Hayaishi O. Immunohistochemical localization of indoleamine 2,3-dioxygenase in the argyrophilic cells of rabbit duodenum and thyroid gland. J Histochem Cytochem. 1981 May;29(5):623–632. doi: 10.1177/29.5.6788834. [DOI] [PubMed] [Google Scholar]
  27. Werner-Felmayer G., Werner E. R., Fuchs D., Hausen A., Reibnegger G., Wachter H. Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts. J Exp Med. 1990 Dec 1;172(6):1599–1607. doi: 10.1084/jem.172.6.1599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Werner E. R., Fuchs D., Hausen A., Reibnegger G., Wachter H. Simultaneous determination of neopterin and creatinine in serum with solid-phase extraction and on-line elution liquid chromatography. Clin Chem. 1987 Nov;33(11):2028–2033. [PubMed] [Google Scholar]
  29. Werner E. R., Werner-Felmayer G., Fuchs D., Hausen A., Reibnegger G., Yim J. J., Pfleiderer W., Wachter H. Tetrahydrobiopterin biosynthetic activities in human macrophages, fibroblasts, THP-1, and T 24 cells. GTP-cyclohydrolase I is stimulated by interferon-gamma, and 6-pyruvoyl tetrahydropterin synthase and sepiapterin reductase are constitutively present. J Biol Chem. 1990 Feb 25;265(6):3189–3192. [PubMed] [Google Scholar]
  30. Wong G. H., Clark-Lewis I., Harris A. W., Schrader J. W. Effect of cloned interferon-gamma on expression of H-2 and Ia antigens on cell lines of hemopoietic, lymphoid, epithelial, fibroblastic and neuronal origin. Eur J Immunol. 1984 Jan;14(1):52–56. doi: 10.1002/eji.1830140110. [DOI] [PubMed] [Google Scholar]
  31. Yim J. J., Brown G. M. Characteristics of guanosine triphosphate cyclohydrolase I purified from Escherichia coli. J Biol Chem. 1976 Aug 25;251(16):5087–5094. [PubMed] [Google Scholar]
  32. Ziegler I., Schott K., Lübbert M., Herrmann F., Schwuléra U., Bacher A. Control of tetrahydrobiopterin synthesis in T lymphocytes by synergistic action of interferon-gamma and interleukin-2. J Biol Chem. 1990 Oct 5;265(28):17026–17030. [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES