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. 1994 Jun;62(6):2277–2284. doi: 10.1128/iai.62.6.2277-2284.1994

Antiparasitic and antiproliferative effects of indoleamine 2,3-dioxygenase enzyme expression in human fibroblasts.

S L Gupta 1, J M Carlin 1, P Pyati 1, W Dai 1, E R Pfefferkorn 1, M J Murphy Jr 1
PMCID: PMC186508  PMID: 8188349

Abstract

Studies were carried out to evaluate the proposed role of indoleamine 2,3-dioxygenase (INDO) induction in the antimicrobial and antiproliferative effects of gamma interferon (IFN-gamma) in human fibroblasts. The INDO cDNA coding region was cloned in the pMEP4 expression vector, containing the metallothionein (MTII) promoter in the sense (+ve) or the antisense (-ve) orientation. Human fibroblasts (GM637) stably transfected with the sense construct expressed INDO activity after treatment with CdCl2 or ZnSO4, but cells transfected with the antisense construct did not. The growth of Chlamydia psittaci was strongly inhibited in INDO +ve cells but not in INDO -ve cells after treatment with Cd2+ or Zn2+. The inhibition correlated with the level of INDO activity induced and could be reversed by the addition of excess tryptophan to the medium. The growth of Toxoplasma gondii was also strongly inhibited in INDO +ve cells but not in INDO -ve cells after treatment with Cd2+. Expression of Cd(2+)-induced INDO activity also inhibited thymidine incorporation and led to cytotoxicity in INDO +ve cells but not in INDO -ve cells. Thus, the induction of INDO activity by IFN-gamma may be an important factor in the antimicrobial and antiproliferative effects of IFN-gamma in human fibroblasts.

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Selected References

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  1. Adams L. B., Hibbs J. B., Jr, Taintor R. R., Krahenbuhl J. L. Microbiostatic effect of murine-activated macrophages for Toxoplasma gondii. Role for synthesis of inorganic nitrogen oxides from L-arginine. J Immunol. 1990 Apr 1;144(7):2725–2729. [PubMed] [Google Scholar]
  2. Belosevic M., Finbloom D. S., Van Der Meide P. H., Slayter M. V., Nacy C. A. Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989 Jul 1;143(1):266–274. [PubMed] [Google Scholar]
  3. Buchmeier N. A., Schreiber R. D. Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7404–7408. doi: 10.1073/pnas.82.21.7404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Byrne G. I., Faubion C. L. Lymphokine-mediated microbistatic mechanisms restrict Chlamydia psittaci growth in macrophages. J Immunol. 1982 Jan;128(1):469–474. [PubMed] [Google Scholar]
  5. Byrne G. I., Lehmann L. K., Landry G. J. Induction of tryptophan catabolism is the mechanism for gamma-interferon-mediated inhibition of intracellular Chlamydia psittaci replication in T24 cells. Infect Immun. 1986 Aug;53(2):347–351. doi: 10.1128/iai.53.2.347-351.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Caplen H. S., Gupta S. L. Differential regulation of a cellular gene by human interferon-gamma and interferon-alpha. J Biol Chem. 1988 Jan 5;263(1):332–339. [PubMed] [Google Scholar]
  7. Carlin J. M., Borden E. C., Byrne G. I. Interferon-induced indoleamine 2,3-dioxygenase activity inhibits Chlamydia psittaci replication in human macrophages. J Interferon Res. 1989 Jun;9(3):329–337. doi: 10.1089/jir.1989.9.329. [DOI] [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. Dai W., Gupta S. L. Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA. Biochem Biophys Res Commun. 1990 Apr 16;168(1):1–8. doi: 10.1016/0006-291x(90)91666-g. [DOI] [PubMed] [Google Scholar]
  10. Farrar M. A., Schreiber R. D. The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol. 1993;11:571–611. doi: 10.1146/annurev.iy.11.040193.003035. [DOI] [PubMed] [Google Scholar]
  11. Feng G. S., Taylor M. W. Interferon gamma-resistant mutants are defective in the induction of indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7144–7148. doi: 10.1073/pnas.86.18.7144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fuchs D., Forsman A., Hagberg L., Larsson M., Norkrans G., Reibnegger G., Werner E. R., Wachter H. Immune activation and decreased tryptophan in patients with HIV-1 infection. J Interferon Res. 1990 Dec;10(6):599–603. doi: 10.1089/jir.1990.10.599. [DOI] [PubMed] [Google Scholar]
  13. Fuchs D., Hausen A., Reibnegger G., Werner E. R., Werner-Felmayer G., Dierich M. P., Wachter H. Interferon-gamma concentrations are increased in sera from individuals infected with human immunodeficiency virus type 1. J Acquir Immune Defic Syndr. 1989;2(2):158–162. [PubMed] [Google Scholar]
  14. Green S. J., Crawford R. M., Hockmeyer J. T., Meltzer M. S., Nacy C. A. Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha. J Immunol. 1990 Dec 15;145(12):4290–4297. [PubMed] [Google Scholar]
  15. Habara-Ohkubo A., Shirahata T., Takikawa O., Yoshida R. Establishment of an antitoxoplasma state by stable expression of mouse indoleamine 2,3-dioxygenase. Infect Immun. 1993 May;61(5):1810–1813. doi: 10.1128/iai.61.5.1810-1813.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hatch T. P. Competition between Chlamydia psittaci and L cells for host isoleucine pools: a limiting factor in chlamydial multiplication. Infect Immun. 1975 Jul;12(1):211–220. doi: 10.1128/iai.12.1.211-220.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heyes M. P., Brew B. J., Martin A., Price R. W., Salazar A. M., Sidtis J. J., Yergey J. A., Mouradian M. M., Sadler A. E., Keilp J. Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status. Ann Neurol. 1991 Feb;29(2):202–209. doi: 10.1002/ana.410290215. [DOI] [PubMed] [Google Scholar]
  18. Heyes M. P., Rubinow D., Lane C., Markey S. P. Cerebrospinal fluid quinolinic acid concentrations are increased in acquired immune deficiency syndrome. Ann Neurol. 1989 Aug;26(2):275–277. doi: 10.1002/ana.410260215. [DOI] [PubMed] [Google Scholar]
  19. Heyes M. P., Saito K., Jacobowitz D., Markey S. P., Takikawa O., Vickers J. H. Poliovirus induces indoleamine-2,3-dioxygenase and quinolinic acid synthesis in macaque brain. FASEB J. 1992 Aug;6(11):2977–2989. doi: 10.1096/fasebj.6.11.1322853. [DOI] [PubMed] [Google Scholar]
  20. Launay J. M., Copel L., Callebert J., Corvaïa N., Lepage E., Bricaire F., Saal F., Peries J. Decreased whole blood 5-hydroxytryptamine (serotonin) in AIDS patients. J Acquir Immune Defic Syndr. 1988;1(4):324–325. [PubMed] [Google Scholar]
  21. Mayer J., Woods M. L., Vavrin Z., Hibbs J. B., Jr Gamma interferon-induced nitric oxide production reduces Chlamydia trachomatis infectivity in McCoy cells. Infect Immun. 1993 Feb;61(2):491–497. doi: 10.1128/iai.61.2.491-497.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Murray H. W. Interferon-gamma, the activated macrophage, and host defense against microbial challenge. Ann Intern Med. 1988 Apr;108(4):595–608. doi: 10.7326/0003-4819-108-4-595. [DOI] [PubMed] [Google Scholar]
  23. Murray H. W. The interferons, macrophage activation, and host defense against nonviral pathogens. J Interferon Res. 1992 Oct;12(5):319–322. doi: 10.1089/jir.1992.12.319. [DOI] [PubMed] [Google Scholar]
  24. Nathan C. F., Hibbs J. B., Jr Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol. 1991 Feb;3(1):65–70. doi: 10.1016/0952-7915(91)90079-g. [DOI] [PubMed] [Google Scholar]
  25. Ozaki Y., Edelstein M. P., Duch D. S. Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1242–1246. doi: 10.1073/pnas.85.4.1242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pfefferkorn E. R., Eckel M., Rebhun S. Interferon-gamma suppresses the growth of Toxoplasma gondii in human fibroblasts through starvation for tryptophan. Mol Biochem Parasitol. 1986 Sep;20(3):215–224. doi: 10.1016/0166-6851(86)90101-5. [DOI] [PubMed] [Google Scholar]
  27. Pfefferkorn E. R., Guyre P. M. Inhibition of growth of Toxoplasma gondii in cultured fibroblasts by human recombinant gamma interferon. Infect Immun. 1984 May;44(2):211–216. doi: 10.1128/iai.44.2.211-216.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pfefferkorn E. R. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan. Proc Natl Acad Sci U S A. 1984 Feb;81(3):908–912. doi: 10.1073/pnas.81.3.908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pfefferkorn E. R., Pfefferkorn L. C. Toxoplasma gondii: isolation and preliminary characterization of temperature-sensitive mutants. Exp Parasitol. 1976 Jun;39(3):365–376. doi: 10.1016/0014-4894(76)90040-0. [DOI] [PubMed] [Google Scholar]
  30. Schwartzman J. D., Gonias S. L., Pfefferkorn E. R. Murine gamma interferon fails to inhibit Toxoplasma gondii growth in murine fibroblasts. Infect Immun. 1990 Mar;58(3):833–834. doi: 10.1128/iai.58.3.833-834.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Suzuki Y., Orellana M. A., Schreiber R. D., Remington J. S. Interferon-gamma: the major mediator of resistance against Toxoplasma gondii. Science. 1988 Apr 22;240(4851):516–518. doi: 10.1126/science.3128869. [DOI] [PubMed] [Google Scholar]
  32. Takikawa O., Kuroiwa T., Yamazaki F., Kido R. Mechanism of interferon-gamma action. Characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-gamma and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity. J Biol Chem. 1988 Feb 5;263(4):2041–2048. [PubMed] [Google Scholar]
  33. Thomas S. M., Garrity L. F., Brandt C. R., Schobert C. S., Feng G. S., Taylor M. W., Carlin J. M., Byrne G. I. IFN-gamma-mediated antimicrobial response. Indoleamine 2,3-dioxygenase-deficient mutant host cells no longer inhibit intracellular Chlamydia spp. or Toxoplasma growth. J Immunol. 1993 Jun 15;150(12):5529–5534. [PubMed] [Google Scholar]
  34. Tyring S., Klimpel G. R., Fleischmann W. R., Jr, Baron S. Direct cytolysis by partially-purified preparations of immune interferon. Int J Cancer. 1982 Jul 15;30(1):59–64. doi: 10.1002/ijc.2910300111. [DOI] [PubMed] [Google Scholar]
  35. Weil J., Epstein C. J., Epstein L. B., Sedmak J. J., Sabran J. L., Grossberg S. E. A unique set of polypeptides is induced by gamma interferon in addition to those induced in common with alpha and beta interferons. Nature. 1983 Feb 3;301(5899):437–439. doi: 10.1038/301437a0. [DOI] [PubMed] [Google Scholar]
  36. Yong S., Lau S. Rapid separation of tryptophan, kynurenines, and indoles using reversed-phase high-performance liquid chromatography. J Chromatogr. 1979 Jul 13;175(2):343–346. doi: 10.1016/s0021-9673(00)89443-1. [DOI] [PubMed] [Google Scholar]
  37. Zhong G. M., Peterson E. M., Czarniecki C. W., Schreiber R. D., de la Maza L. M. Role of endogenous gamma interferon in host defense against Chlamydia trachomatis infections. Infect Immun. 1989 Jan;57(1):152–157. doi: 10.1128/iai.57.1.152-157.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. de la Maza L. M., Peterson E. M. Dependence of the in vitro antiproliferative activity of recombinant human gamma-interferon on the concentration of tryptophan in culture media. Cancer Res. 1988 Jan 15;48(2):346–350. [PubMed] [Google Scholar]

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