Interferon Type I and II Antagonism: A Novel Regulatory Mechanism of Indoleamine Dioxygenase Induction in Human Peripheral Blood Monocytes and Peritoneal Macrophages

  • Y. Ozaki
  • E. C. Borden
  • R. V. Smalley
  • R. R. Brown
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 294)


Antiproliferative effects of interferon (IFN)-γ in vitro on some tumor cells (de 1a Maza and Peterson, 1988; Ozaki et al., 1988a; Takikawa et al., 1988), Chlamvdia psittaci (Byrne et al., 1986) and Toxoplasma gondii (Pfefferkorn, 1984) are mediated by deprivation of tryptophan (TRP) which results when the cytokine induces indoleamine 2, 3-dioxygenase (IDO) activity in the cancer or host cells. Among the human peripheral blood mononuclear cells as well as granulocytes, IFN-mediated induction of IDO is localized in peripheral blood monocytes (PBM) or PBM-derived macrophages (DM; Ozaki et al., 1987a; Werner et al., 1987; Rubin et al., 1988; Carlin et al., 1989), however the mechanism of control of extra-hepatic TRP metabolism by the IFNs has not been fully elucidated in these cells or in peritoneal macrophages (PM). The occurrence of IFN type I antagonism against IFN type II-elicited release of H202, expression of 1a antigen as well as mannosyl/fucosyl receptors, high-affinity binding of type II IFN, and tumor cell killing by macrophages has been reported (Ling et al., 1985; Ezekowitz et al., 1986; Garotta et al., 1986; Inaba et al., 1986; Pace 1987; Yoshida et al., 1988). However, the down-regulation of IFN-7-mediated induction of IDO by IFN-α, IFN-β and 12-0-tetradecanoylphorbol-13 acetate (TPA) has never been documented. To this end, we report clear differences between PBMs, DMs and PMs in response to IFNs as well as to a potent tumor promoter, TPA. Further, the occurrence of a novel regulatory mechanism of TRP metabolism through modulation of type II IFN-induced IDO activity by type I IFNs or by TPA, in monocytes and macrophages is demonstrated in this report.


Peritoneal Macrophage Murine Macrophage Tumor Cell Killing Human Peripheral Blood Mononuclear Cell Human Peripheral Blood Monocyte 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Argov, S., Hebdon, M., Cuatrecasas, P., and Koren, H.S., 1985, Phorbol ester-induced lymphocyte adherence: selective action on NK cells, J. Immunol., 134: 2215–2222.PubMedGoogle Scholar
  2. Boyum, A., 1968, Isolation of mononuclear cells and granulocytes from human blood, Scand. J. Clin. Lab. Invest., Suppl. 97, 21: 77–89.CrossRefGoogle Scholar
  3. Brown, R.R., Borden, E.C., Sondel, P.M., and Lee, C.M., 1987, Effects of interferons and interleukin-2 on tryptophan metabolism in humans, in: “Progress in Tryptophan and Serotonin Research”, Bender, D.A., Joseph, M.H., Kochen, W., and Steinhart, H., eds., de Gruyter, Berlin, pp. 19–26.Google Scholar
  4. Byrne, G., Lehmann, L., Kirschbaum, J., Borden, E., Lee, C., and Brown, R., 1986, Induction of tryptophan degradation in vitro and in vivo: a γinterferon-stimulated activity, J. Interferon Res., 6: 389–396.PubMedCrossRefGoogle Scholar
  5. Carlin, J.M., Borden, E.C., Sondel, P.M., and Byrne, G.I., 1989, Interferon-induced indoleamine 2, 3-dioxygenase activity in human mononuclear phagocytes, J. Leukocyte Biol., 45: 29–34.PubMedGoogle Scholar
  6. Datta, S.P., Brown, R.R., Borden, E.C., Sondel, P.M., and Trump, D.L., 1987, Interferon and interleukin-2 induced changes in tryptophan and neopterin metabolism: possible markers for biologically effective doses, Proc. Am. Assoc. Cancer Res., 28: 338.Google Scholar
  7. de laMaza, L.M., and Peterson, E.M., 1988, Dependence of the in vitro anti-proliferative activity of recombinant human γ-interferon on the concentration of tryptophan in culture media, Cancer Res., 48: 346–350.Google Scholar
  8. Ezekowitz, R.A.B., Hill, M., and Gordon, S., 1986, Interferon α/β selectively antagonizes down-regulation of mannosyl-fucosyl receptors on activated macrophages by interferon-γ, Biochem. Biophys. Res. Commun., 136: 737–744.PubMedCrossRefGoogle Scholar
  9. Finbloom, D.S., and Wahl, L.M., 1989, Characterization of a novel low affinity receptor for IFN-γ on adherent human monocytes by radioligand binding studies and chemical cross-linking, J. Immunol., 142: 2314–2320.PubMedGoogle Scholar
  10. Garotta, G., Talmadge, K.W., Pink, R.L., Dewald, B., and Baggiolini, M., 1986, Functional antagonism between type I and type II interferons on human macrophages, Biochem. Biophys. Res. Commun., 140: 948–955.PubMedCrossRefGoogle Scholar
  11. Gessani, S., Baglioni, C., Puddu, P., Di Marzio, P., and Belardelli, F., 1988, Bacterial lipopolysaccharide and IFN-γ induce transcription of IFN-β mRNA and IFN secretion in murine macrophages, J. Interferon Res., Suppl. 1, 8: S50.Google Scholar
  12. Hoover, D.L., Gendelman, H., Vargo, M., and Metzer, M.S., 1989, IL4 and IFN-gamma inhibit replication of human peripheral blood monocytes, FASEB J., 3: A822.Google Scholar
  13. Inaba, K., Kitaura, M., Kato, T., Watanabe, Y., Kawade, Y., and Muramatsu, S., 1986, Contrasting effect of α/β-and γ-interferons on expression of macrophage Ia antigens, J. Exp. Med., 163: 1030–1037.PubMedCrossRefGoogle Scholar
  14. Johnson, H.M., and Torres, B.A., 1985, Mechanism of calcium ionophore A23187-induced priming of bone marrow-derived macrophages for tumor cell killing: Relationship to priming by interferon, Proc. Natl. Acad. Sci. USA, 82: 5959–5962.PubMedCrossRefGoogle Scholar
  15. Leyko, M.A., and Varesio, L., 1989, Role for tryptophan and its metabolites in the activation of macrophage tumor cytotoxicity, FASEB J., 3: A822.Google Scholar
  16. Ling, P.D., Warren, M.K., and Vogel, S.N., 1985, Antagonistic effect of interferon-β on the interferon-γ-induced expression of Ia antigen in murine macrophages, J. Immunol., 135: 1857–1863.PubMedGoogle Scholar
  17. Ozaki, Y., Edelstein, M., and Duch, D., 1987a, The actions of interferon and antiinflammatory agents on induction of indoleamine 2,3-dioxygenase in human peripheral blood monocytes, Biochem. Biophys. Res. Commun., 144: 1147–1153.CrossRefGoogle Scholar
  18. Ozaki, Y., Edelstein, M., and Duch, D., 1988a, Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon-γ, Proc. Natl. Acad. Sci. USA, 85: 1242–1246.PubMedCrossRefGoogle Scholar
  19. Ozaki, Y., Edelstein, M., and Duch, D., 1988b, Induction of indoleamine 2,3-dioxygenase by interferon-γ in tumor cells: potentiation by phorbol ester, J. Interferon Res., Suppl. 1, 8: S104.Google Scholar
  20. Ozaki, Y., Nichol, C.A., and Duch, D., 1987b, Utilization of dihydroflavin mononucleotide and Superoxide anion for the decyclization of L-tryptophan by murine epididymal indoleamine 2, 3-dioxygenase, Arch. Biochem. Biophys., 257: 207–216.PubMedCrossRefGoogle Scholar
  21. Ozaki, Y., Reinhard, J.F., and Nichol, C.A., 1986, Cofactor activity of dihydroflavin mononucleotide and tetrahydrobiopterin for murine epididymal indoleamine 2,3-dioxygenase, Biochem. Biophys. Res. Commun., 137: 1106–1111.PubMedCrossRefGoogle Scholar
  22. Pace, J.L., Mackay, R.J., and Hayes, M.P., 1987, Suppressive effect of inter-feron-β on development of tumoricidal activity in mouse macrophages, J. Leukocyte Biol., 41: 257–262.PubMedGoogle Scholar
  23. Pfefferkorn, E., 1984, Interferon-7 blocks the growth of Toxoplasma gondii in human fibroblasts by inducing host cell to degrade tryptophan, Proc. Natl. Acad. Sci. USA, 81: 908–912.PubMedCrossRefGoogle Scholar
  24. Rubin, R.Y., Anderson, S.L., Hellermann, G.R., Richardson, N.K., Lunn, R.M., and Valinsky, J.E., 1988, The development of antibody to the interferon-induced indoleamine 2,3-dioxygenase and the study of the regulation of its synthesis, J. Interferon Res., 8: 691–702.PubMedCrossRefGoogle Scholar
  25. Sternberg, E.M., Trial, J., and Parker, C.W., 1986, Effect of serotonin on murine macrophages: suppression of Ia expression by serotonin and its reversal by 5HT2 serotoninergic receptor antagonists, J. Immunol., 137: 276–282.PubMedGoogle Scholar
  26. Takikawa, O., Kuroiwa, T., Yamazaki, F., and Kido, R., 1988, Mechanism of interferon-γ action: characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-γ and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity, J. Biol. Chem., 263: 2041–2048.PubMedGoogle Scholar
  27. van Furth, R., Raeburn, J.A., and van Zwet, T.L., 1979, Characteristics of human mononuclear phagocytes, Blood, 54: 485–500.PubMedGoogle Scholar
  28. Werner, E.R., Bitterlich, G., Fuchs, D., Hausen, A., Reibnegger, G., Szabo, G., Dierich, P.M., and Wachter, H., 1987, Human macrophages degrade tryptophan upon induction by interferon-γ, Life Sci., 41: 273–280.PubMedCrossRefGoogle Scholar
  29. Yoshida, R., Murray, H.W., and Nathan, C.F., 1988, Agonist and antagonist effects of interferon a and β on activation of human macrophages: two classes of interferon γ receptors and blockade of the high-affinity sites by interferon α or β, J. Exp. Med., 167: 1171–1185.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Y. Ozaki
    • 1
  • E. C. Borden
    • 1
  • R. V. Smalley
    • 1
  • R. R. Brown
    • 1
  1. 1.University of Wisconsin Clinical Cancer CenterMadisonUSA

Personalised recommendations