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. 1987 Oct;80(4):1009–1016. doi: 10.1172/JCI113153

Recombinant interferon gamma augments phagocyte superoxide production and X-chronic granulomatous disease gene expression in X-linked variant chronic granulomatous disease.

R A Ezekowitz 1, S H Orkin 1, P E Newburger 1
PMCID: PMC442339  PMID: 2821069

Abstract

We examined the potential of interferon gamma (IFN-gamma) to ameliorate the physiologic defect of chronic granulomatous disease (CGD) by studying its effects on CGD phagocyte superoxide generation, NADPH oxidase kinetics, cytochrome b559 content, and expression of X-CGD (the gene for the X-linked disease). Granulocytes and macrophages from three patients in two kindreds with "variant" X-linked CGD (i.e., with very low, but detectable, baseline superoxide-generating activity) responded to IFN-gamma with enhanced nitroblue tetrazolium reduction and two- to eightfold increases in superoxide generation. IFN-gamma did not augment the respiratory burst activity of phagocytes from patients with "classic" CGD (i.e., no detectable baseline superoxide generation) or autosomal variant CGD. Incubation of a responding patient's granulocytes with IFN-gamma nearly doubled the maximal velocity for the NADPH oxidase, but did not change its abnormal Michaelis constant. Although the interferon-treated CGD granulocytes produced superoxide at a rate 40% of normal, the cytochrome b spectrum remained undetectable. IFN-gamma treatment of cultured monocytes from an IFN-gamma-responsive CGD patient increased the steady state level of RNA transcripts from the X-CGD gene from barely detectable up to approximately 5% of normal.

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Selected References

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

  1. Babior B. M. Oxidants from phagocytes: agents of defense and destruction. Blood. 1984 Nov;64(5):959–966. [PubMed] [Google Scholar]
  2. Baehner R. L., Nathan D. G. Leukocyte oxidase: defective activity in chronic granulomatous disease. Science. 1967 Feb 17;155(3764):835–836. doi: 10.1126/science.155.3764.835. [DOI] [PubMed] [Google Scholar]
  3. Berton G., Zeni L., Cassatella M. A., Rossi F. Gamma interferon is able to enhance the oxidative metabolism of human neutrophils. Biochem Biophys Res Commun. 1986 Aug 14;138(3):1276–1282. doi: 10.1016/s0006-291x(86)80421-1. [DOI] [PubMed] [Google Scholar]
  4. Borregaard N., Cross A. R., Herlin T., Jones O. T., Segal A. W., Valerius N. H. A variant form of X-linked chronic granulomatous disease with normal nitroblue tetrazolium slide test and cytochrome b. Eur J Clin Invest. 1983 Jun;13(3):243–248. doi: 10.1111/j.1365-2362.1983.tb00095.x. [DOI] [PubMed] [Google Scholar]
  5. Cassatella M. A., Della Bianca V., Berton G., Rossi F. Activation by gamma interferon of human macrophage capability to produce toxic oxygen molecules is accompanied by decreased Km of the superoxide-generating NADPH oxidase. Biochem Biophys Res Commun. 1985 Nov 15;132(3):908–914. doi: 10.1016/0006-291x(85)91893-5. [DOI] [PubMed] [Google Scholar]
  6. Cohen H. J., Chovaniec M. E. Superoxide generation by digitonin-stimulated guinea pig granulocytes. A basis for a continuous assay for monitoring superoxide production and for the study of the activation of the generating system. J Clin Invest. 1978 Apr;61(4):1081–1087. doi: 10.1172/JCI109007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Curnutte J. T., Whitten D. M., Babior B. M. Defective superoxide production by granulocytes from patients with chronic granulomatous disease. N Engl J Med. 1974 Mar 14;290(11):593–597. doi: 10.1056/NEJM197403142901104. [DOI] [PubMed] [Google Scholar]
  8. Ezekowitz R. A., Hill M., Gordon S. Interferon alpha/beta selectively antagonises down-regulation of mannosyl-fucosyl receptors on activated macrophages by interferon gamma. Biochem Biophys Res Commun. 1986 Apr 29;136(2):737–744. doi: 10.1016/0006-291x(86)90501-2. [DOI] [PubMed] [Google Scholar]
  9. Ezekowitz R. A., Sim R. B., MacPherson G. G., Gordon S. Interaction of human monocytes, macrophages, and polymorphonuclear leukocytes with zymosan in vitro. Role of type 3 complement receptors and macrophage-derived complement. J Clin Invest. 1985 Dec;76(6):2368–2376. doi: 10.1172/JCI112249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  11. Ginsburg D., Handin R. I., Bonthron D. T., Donlon T. A., Bruns G. A., Latt S. A., Orkin S. H. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science. 1985 Jun 21;228(4706):1401–1406. doi: 10.1126/science.3874428. [DOI] [PubMed] [Google Scholar]
  12. Lew P. D., Southwick F. S., Stossel T. P., Whitin J. C., Simons E., Cohen H. J. A variant of chronic granulomatous disease: deficient oxidative metabolism due to a low-affinity NADPH oxidase. N Engl J Med. 1981 Nov 26;305(22):1329–1333. doi: 10.1056/NEJM198111263052207. [DOI] [PubMed] [Google Scholar]
  13. Light D. R., Walsh C., O'Callaghan A. M., Goetzl E. J., Tauber A. I. Characteristics of the cofactor requirements for the superoxide-generating NADPH oxidase of human polymorphonuclear leukocytes. Biochemistry. 1981 Mar 17;20(6):1468–1476. doi: 10.1021/bi00509a010. [DOI] [PubMed] [Google Scholar]
  14. McPhail L. C., Clayton C. C., Snyderman R. The NADPH oxidase of human polymorphonuclear leukocytes. Evidence for regulation by multiple signals. J Biol Chem. 1984 May 10;259(9):5768–5775. [PubMed] [Google Scholar]
  15. McPhail L. C., Snyderman R. Activation of the respiratory burst enzyme in human polymorphonuclear leukocytes by chemoattractants and other soluble stimuli. Evidence that the same oxidase is activated by different transductional mechanisms. J Clin Invest. 1983 Jul;72(1):192–200. doi: 10.1172/JCI110957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Michelson A. M., Markham A. F., Orkin S. H. Isolation and DNA sequence of a full-length cDNA clone for human X chromosome-encoded phosphoglycerate kinase. Proc Natl Acad Sci U S A. 1983 Jan;80(2):472–476. doi: 10.1073/pnas.80.2.472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Nathan C. F., Horowitz C. R., de la Harpe J., Vadhan-Raj S., Sherwin S. A., Oettgen H. F., Krown S. E. Administration of recombinant interferon gamma to cancer patients enhances monocyte secretion of hydrogen peroxide. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8686–8690. doi: 10.1073/pnas.82.24.8686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nathan C. F., Kaplan G., Levis W. R., Nusrat A., Witmer M. D., Sherwin S. A., Job C. K., Horowitz C. R., Steinman R. M., Cohn Z. A. Local and systemic effects of intradermal recombinant interferon-gamma in patients with lepromatous leprosy. N Engl J Med. 1986 Jul 3;315(1):6–15. doi: 10.1056/NEJM198607033150102. [DOI] [PubMed] [Google Scholar]
  19. Nathan C. F. Mechanisms of macrophage antimicrobial activity. Trans R Soc Trop Med Hyg. 1983;77(5):620–630. doi: 10.1016/0035-9203(83)90190-6. [DOI] [PubMed] [Google Scholar]
  20. Nathan C. F., Murray H. W., Wiebe M. E., Rubin B. Y. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med. 1983 Sep 1;158(3):670–689. doi: 10.1084/jem.158.3.670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nathan C. F., Tsunawaki S. Secretion of toxic oxygen products by macrophages: regulatory cytokines and their effects on the oxidase. Ciba Found Symp. 1986;118:211–230. doi: 10.1002/9780470720998.ch14. [DOI] [PubMed] [Google Scholar]
  22. Newburger P. E., Luscinskas F. W., Ryan T., Beard C. J., Wright J., Platt O. S., Simons E. R., Tauber A. I. Variant chronic granulomatous disease: modulation of the neutrophil defect by severe infection. Blood. 1986 Oct;68(4):914–919. [PubMed] [Google Scholar]
  23. Newburger P. E., Speier C., Borregaard N., Walsh C. E., Whitin J. C., Simons E. R. Development of the superoxide-generating system during differentiation of the HL-60 human promyelocytic leukemia cell line. J Biol Chem. 1984 Mar 25;259(6):3771–3776. [PubMed] [Google Scholar]
  24. Ohno Y., Buescher E. S., Roberts R., Metcalf J. A., Gallin J. I. Reevaluation of cytochrome b and flavin adenine dinucleotide in neutrophils from patients with chronic granulomatous disease and description of a family with probable autosomal recessive inheritance of cytochrome b deficiency. Blood. 1986 Apr;67(4):1132–1138. [PubMed] [Google Scholar]
  25. Parkos C. A., Allen R. A., Cochrane C. G., Jesaitis A. J. Purified cytochrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weights of 91,000 and 22,000. J Clin Invest. 1987 Sep;80(3):732–742. doi: 10.1172/JCI113128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pember S. O., Heyl B. L., Kinkade J. M., Jr, Lambeth J. D. Cytochrome b558 from (bovine) granulocytes. Partial purification from Triton X-114 extracts and properties of the isolated cytochrome. J Biol Chem. 1984 Aug 25;259(16):10590–10595. [PubMed] [Google Scholar]
  27. Royer-Pokora B., Kunkel L. M., Monaco A. P., Goff S. C., Newburger P. E., Baehner R. L., Cole F. S., Curnutte J. T., Orkin S. H. Cloning the gene for an inherited human disorder--chronic granulomatous disease--on the basis of its chromosomal location. Nature. 1986 Jul 3;322(6074):32–38. doi: 10.1038/322032a0. [DOI] [PubMed] [Google Scholar]
  28. Segal A. W. Absence of both cytochrome b-245 subunits from neutrophils in X-linked chronic granulomatous disease. Nature. 1987 Mar 5;326(6108):88–91. doi: 10.1038/326088a0. [DOI] [PubMed] [Google Scholar]
  29. Segal A. W., Cross A. R., Garcia R. C., Borregaard N., Valerius N. H., Soothill J. F., Jones O. T. Absence of cytochrome b-245 in chronic granulomatous disease. A multicenter European evaluation of its incidence and relevance. N Engl J Med. 1983 Feb 3;308(5):245–251. doi: 10.1056/NEJM198302033080503. [DOI] [PubMed] [Google Scholar]
  30. Segal A. W., Heyworth P. G., Cockcroft S., Barrowman M. M. Stimulated neutrophils from patients with autosomal recessive chronic granulomatous disease fail to phosphorylate a Mr-44,000 protein. Nature. 1985 Aug 8;316(6028):547–549. doi: 10.1038/316547a0. [DOI] [PubMed] [Google Scholar]
  31. Segal A. W., Jones O. T., Webster D., Allison A. C. Absence of a newly described cytochrome b from neutrophils of patients with chronic granulomatous disease. Lancet. 1978 Aug 26;2(8087):446–449. doi: 10.1016/s0140-6736(78)91445-9. [DOI] [PubMed] [Google Scholar]
  32. Segal A. W. Variations on the theme of chronic granulomatous disease. Lancet. 1985 Jun 15;1(8442):1378–1383. doi: 10.1016/s0140-6736(85)91796-9. [DOI] [PubMed] [Google Scholar]
  33. Seger R. A., Tiefenauer L., Matsunaga T., Wildfeuer A., Newburger P. E. Chronic granulomatous disease due to granulocytes with abnormal NADPH oxidase activity and deficient cytochrome-b. Blood. 1983 Mar;61(3):423–428. [PubMed] [Google Scholar]
  34. Shalaby M. R., Aggarwal B. B., Rinderknecht E., Svedersky L. P., Finkle B. S., Palladino M. A., Jr Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985 Sep;135(3):2069–2073. [PubMed] [Google Scholar]
  35. Shurin S. B., Cohen H. J., Whitin J. C., Newburger P. E. Impaired granulocyte superoxide production and prolongation of the respiratory burst due to a low-affinity NADPH-dependent oxidase. Blood. 1983 Sep;62(3):564–571. [PubMed] [Google Scholar]
  36. Styrt B., Klempner M. S. Late-presenting variant of chronic granulomatous disease. Pediatr Infect Dis. 1984 Nov-Dec;3(6):556–559. doi: 10.1097/00006454-198411000-00015. [DOI] [PubMed] [Google Scholar]
  37. Suzuki Y., Lehrer R. I. NAD(P)H oxidase activity in human neutrophils stimulated by phorbol myristate acetate. J Clin Invest. 1980 Dec;66(6):1409–1418. doi: 10.1172/JCI109994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Szuro-Sudol A., Murray H. W., Nathan C. F. Suppression of macrophage antimicrobial activity by a tumor cell product. J Immunol. 1983 Jul;131(1):384–387. [PubMed] [Google Scholar]
  39. Tauber A. I., Borregaard N., Simons E., Wright J. Chronic granulomatous disease: a syndrome of phagocyte oxidase deficiencies. Medicine (Baltimore) 1983 Sep;62(5):286–309. [PubMed] [Google Scholar]
  40. Ward P. A., Becker E. L. The deactivation of rabbit neutrophils by chemotactic factor and the nature of the activatable esterase. J Exp Med. 1968 Apr 1;127(4):693–709. doi: 10.1084/jem.127.4.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zimmerli W., Seligmann B., Gallin J. I. Exudation primes human and guinea pig neutrophils for subsequent responsiveness to the chemotactic peptide N-formylmethionylleucylphenylalanine and increases complement component C3bi receptor expression. J Clin Invest. 1986 Mar;77(3):925–933. doi: 10.1172/JCI112391. [DOI] [PMC free article] [PubMed] [Google Scholar]

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