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. 1988 Mar 1;167(3):1171–1185. doi: 10.1084/jem.167.3.1171

Agonist and antagonist effects of interferon alpha and beta on activation of human macrophages. Two classes of interferon gamma receptors and blockade of the high-affinity sites by interferon alpha or beta

PMCID: PMC2188875  PMID: 2965208

Abstract

H2O2-releasing capacity and limited antitoxoplasma activity could be induced in human macrophages (derived from monocytes cultured greater than or equal to 5 d) but not in monocytes themselves (cells cultured less than or equal to 4 d) by a further 3-d incubation with pure natural or rIFN-alpha or -beta. More than 3 pM (10 U/ml) of these IFNs was required, with greatest effects at approximately 300 pM (10(3) U/ml). At 300 pM, H2O2-releasing capacity was enhanced 4.4 +/- 1.6-fold over medium control (mean +/- SD for natural INF-alpha, rIFN-alpha A, rIFN-alpha D, and rIFN-beta) compared to an 8.4 +/- 4.8-fold increase with rIFN-gamma (100 pM, 100 U/ml) in the same experiments. Unexpectedly, low concentrations of IFN-alpha or -beta (3 fM-300 pM) blocked induction of H2O2-releasing capacity by rIFN-gamma (10 pM), with a 50% inhibitory dose of approximately 80 fM. However, IFN-alpha or -beta (3 fM-300 pM) could not inhibit the effect of higher concentrations of rIFN-gamma (1 nM). In contrast to results with monocytes or young macrophages, Scatchard plots of binding of 125I-rIFN- gamma to mature macrophages (day 8 of culture) indicated two classes of binding sites: approximately 2,000 high-affinity sites (Kd approximately 0.43 nM) and approximately 23,000 low-affinity sites (Kd approximately 6.4 nM) per cell. Binding of 125I-rIFN-gamma to the high- but not the low-affinity sites was blocked by simultaneously added IFN- alpha or -beta, with a 50% inhibitory dose of approximately 2 U/0.25 ml (approximately 2 pM), or reversed by subsequently added IFN-alpha or - beta. Thus, differentiation of human mononuclear phagocytes in vitro is accompanied by the emergence of (a) an agonist response to submicromolar concentrations of IFN-alpha or -beta, (b) antagonism of the effect of picomolar IFN-gamma by femtomolar IFN-alpha or -beta, (c) two classes of IFN-gamma-Rs, and (d) nonstimulatory binding of IFN- alpha or -beta to the high- but not the low-affinity IFN-gamma-Rs, with higher affinity than rIFN-gamma itself. We speculate that traces of IFN- alpha or -beta derived from stromal cells, parenchymal cells, or resident macrophages may dampen the activation of mature tissue macrophages by the small amounts of IFN-gamma that diffuse from inflammatory sites into normal tissues. Such a mechanism could constrain the potentially destructive phenomenon of macrophage activation to areas where monocytes have recently immigrated and/or the concentration of IFNs is high.

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Selected References

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

  1. Aiyer R. A., Serrano L. E., Jones P. P. Interferon-gamma binds to high and low affinity receptor components on murine macrophages. J Immunol. 1986 May 1;136(9):3329–3334. [PubMed] [Google Scholar]
  2. Anderson P., Yip Y. K., Vilcek J. Human interferon-gamma is internalized and degraded by cultured fibroblasts. J Biol Chem. 1983 May 25;258(10):6497–6502. [PubMed] [Google Scholar]
  3. Anderson P., Yip Y. K., Vilcek J. Specific binding of 125I-human interferon-gamma to high affinity receptors on human fibroblasts. J Biol Chem. 1982 Oct 10;257(19):11301–11304. [PubMed] [Google Scholar]
  4. Celada A., Allen R., Esparza I., Gray P. W., Schreiber R. D. Demonstration and partial characterization of the interferon-gamma receptor on human mononuclear phagocytes. J Clin Invest. 1985 Dec;76(6):2196–2205. doi: 10.1172/JCI112228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Czarniecki C. W., Fennie C. W., Powers D. B., Estell D. A. Synergistic antiviral and antiproliferative activities of Escherichia coli-derived human alpha, beta, and gamma interferons. J Virol. 1984 Feb;49(2):490–496. doi: 10.1128/jvi.49.2.490-496.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. De la Harpe J., Nathan C. F. A semi-automated micro-assay for H2O2 release by human blood monocytes and mouse peritoneal macrophages. J Immunol Methods. 1985 Apr 22;78(2):323–336. doi: 10.1016/0022-1759(85)90089-4. [DOI] [PubMed] [Google Scholar]
  7. DeGrado W. F., Wasserman Z. R., Chowdhry V. Sequence and structural homologies among type I and type II interferons. Nature. 1982 Nov 25;300(5890):379–381. doi: 10.1038/300379a0. [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. Finbloom D. S., Hoover D. L., Wahl L. M. The characteristics of binding of human recombinant interferon-gamma to its receptor on human monocytes and human monocyte-like cell lines. J Immunol. 1985 Jul;135(1):300–305. [PubMed] [Google Scholar]
  10. Fleit H. B., Rabinovitch M. Production of interferon by in vitro derived bone marrow macrophages. Cell Immunol. 1981 Jan 15;57(2):495–504. doi: 10.1016/0008-8749(81)90107-6. [DOI] [PubMed] [Google Scholar]
  11. Garotta G., Talmadge K. W., Pink J. R., Dewald B., Baggiolini M. Functional antagonism between type I and type II interferons on human macrophages. Biochem Biophys Res Commun. 1986 Nov 14;140(3):948–954. doi: 10.1016/0006-291x(86)90727-8. [DOI] [PubMed] [Google Scholar]
  12. Hannigan G. E., Fish E. N., Williams B. R. Modulation of human interferon-alpha receptor expression by human interferon-gamma. J Biol Chem. 1984 Jul 10;259(13):8084–8086. [PubMed] [Google Scholar]
  13. Hannigan G. E., Gewert D. R., Williams B. R. Characterization and regulation of alpha-interferon receptor expression in interferon-sensitive and -resistant human lymphoblastoid cells. J Biol Chem. 1984 Aug 10;259(15):9456–9460. [PubMed] [Google Scholar]
  14. Inaba K., Kitaura M., Kato T., Watanabe Y., Kawade Y., Muramatsu S. Contrasting effect of alpha/beta- and gamma-interferons on expression of macrophage Ia antigens. J Exp Med. 1986 Apr 1;163(4):1030–1035. doi: 10.1084/jem.163.4.1030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  16. Ling P. D., Warren M. K., Vogel S. N. Antagonistic effect of interferon-beta on the interferon-gamma-induced expression of Ia antigen in murine macrophages. J Immunol. 1985 Sep;135(3):1857–1863. [PubMed] [Google Scholar]
  17. Littman S. J., Faltynek C. R., Baglioni C. Binding of human recombinant 125I-interferon gamma to receptors on human cells. J Biol Chem. 1985 Jan 25;260(2):1191–1195. [PubMed] [Google Scholar]
  18. Mokoena T., Gordon S. Human macrophage activation. Modulation of mannosyl, fucosyl receptor activity in vitro by lymphokines, gamma and alpha interferons, and dexamethasone. J Clin Invest. 1985 Feb;75(2):624–631. doi: 10.1172/JCI111740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Moore R. N., Pitruzzello F. J., Larsen H. S., Rouse B. T. Feedback regulation of colony-stimulating factor (CSF-1)-induced macrophage proliferation by endogenous E prostaglandins and interferon-alpha/beta. J Immunol. 1984 Aug;133(2):541–543. [PubMed] [Google Scholar]
  20. Murray H. W., Juangbhanich C. W., Nathan C. F., Cohn Z. A. Macrophage oxygen-dependent antimicrobial activity. II. The role of oxygen intermediates. J Exp Med. 1979 Oct 1;150(4):950–964. doi: 10.1084/jem.150.4.950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nakagawara A., Nathan C. F. A simple method for counting adherent cells: application to cultured human monocytes, macrophages and multinucleated giant cells. J Immunol Methods. 1983 Jan 28;56(2):261–268. doi: 10.1016/0022-1759(83)90418-0. [DOI] [PubMed] [Google Scholar]
  22. Nakagawara A., Nathan C. F., Cohn Z. A. Hydrogen peroxide metabolism in human monocytes during differentiation in vitro. J Clin Invest. 1981 Nov;68(5):1243–1252. doi: 10.1172/JCI110370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nathan C. F., Prendergast T. J., Wiebe M. E., Stanley E. R., Platzer E., Remold H. G., Welte K., Rubin B. Y., Murray H. W. Activation of human macrophages. Comparison of other cytokines with interferon-gamma. J Exp Med. 1984 Aug 1;160(2):600–605. doi: 10.1084/jem.160.2.600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Orchansky P., Rubinstein M., Fischer D. G. The interferon-gamma receptor in human monocytes is different from the one in nonhematopoietic cells. J Immunol. 1986 Jan;136(1):169–173. [PubMed] [Google Scholar]
  25. Pace J. L., MacKay R. J., Hayes M. P. Suppressive effect of interferon-beta on development of tumoricidal activity in mouse macrophages. J Leukoc Biol. 1987 Mar;41(3):257–263. doi: 10.1002/jlb.41.3.257. [DOI] [PubMed] [Google Scholar]
  26. Pace J. L., Russell S. W., LeBlanc P. A., Murasko D. M. Comparative effects of various classes of mouse interferons on macrophage activation for tumor cell killing. J Immunol. 1985 Feb;134(2):977–981. [PubMed] [Google Scholar]
  27. Pawlowski N. A., Kaplan G., Hamill A. L., Cohn Z. A., Scott W. A. Arachidonic acid metabolism by human monocytes. Studies with platelet-depleted cultures. J Exp Med. 1983 Aug 1;158(2):393–412. doi: 10.1084/jem.158.2.393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pestka S., Baron S. Definition and classification of the interferons. Methods Enzymol. 1981;78(Pt A):3–14. doi: 10.1016/0076-6879(81)78091-1. [DOI] [PubMed] [Google Scholar]
  29. Rashidbaigi A., Kung H. F., Pestka S. Characterization of receptors for immune interferon in U937 cells with 32P-labeled human recombinant immune interferon. J Biol Chem. 1985 Jul 15;260(14):8514–8519. [PubMed] [Google Scholar]
  30. Sarkar F. H., Gupta S. L. Receptors for human gamma interferon: binding and crosslinking of 125I-labeled recombinant human gamma interferon to receptors on WISH cells. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5160–5164. doi: 10.1073/pnas.81.16.5160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Secher D. S., Burke D. C. A monoclonal antibody for large-scale purification of human leukocyte interferon. Nature. 1980 Jun 12;285(5765):446–450. doi: 10.1038/285446a0. [DOI] [PubMed] [Google Scholar]
  32. Thompson M. R., Zhang Z., Fournier A., Tan Y. H. Characterization of human beta-interferon-binding sites on human cells. J Biol Chem. 1985 Jan 10;260(1):563–567. [PubMed] [Google Scholar]
  33. Unkeless J. C., Healey G. A. Quantitation of proteins and internal antigen pools by a monoclonal sandwich radioimmune assay. J Immunol Methods. 1983;56(1):1–11. doi: 10.1016/0022-1759(83)90043-1. [DOI] [PubMed] [Google Scholar]
  34. Vogel S. N., English K. E., Fertsch D., Fultz M. J. Differential modulation of macrophage membrane markers by interferon: analysis of Fc and C3b receptors, Mac-1 and Ia antigen expression. J Interferon Res. 1983;3(2):153–160. doi: 10.1089/jir.1983.3.153. [DOI] [PubMed] [Google Scholar]
  35. Vogel S. N., Fertsch D. Endogenous interferon production by endotoxin-responsive macrophages provides an autostimulatory differentiation signal. Infect Immun. 1984 Aug;45(2):417–423. doi: 10.1128/iai.45.2.417-423.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wahl L. M., Katona I. M., Wilder R. L., Winter C. C., Haraoui B., Scher I., Wahl S. M. Isolation of human mononuclear cell subsets by counterflow centrifugal elutriation (CCE). I. Characterization of B-lymphocyte-, T-lymphocyte-, and monocyte-enriched fractions by flow cytometric analysis. Cell Immunol. 1984 May;85(2):373–383. doi: 10.1016/0008-8749(84)90251-x. [DOI] [PubMed] [Google Scholar]

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