Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 May;91(5):2031–2039. doi: 10.1172/JCI116425

Interferon-gamma inhibits macrophage apolipoprotein E production by posttranslational mechanisms.

K Brand 1, N Mackman 1, L K Curtiss 1
PMCID: PMC288201  PMID: 8486772

Abstract

Macrophage-derived apolipoprotein (apo) E and multimers of a synthetic apo E-peptide display monokine-like functions by inhibiting mitogen- or antigen-driven lymphocyte proliferation. This study demonstrated how the target lymphocyte itself can modulate macrophage apo E production. The lymphokine interferon-gamma (IFN) dramatically inhibited the accumulation of apo E in the supernatant of human monocytic THP-1 cells when present during phorbol myristate acetate-induced differentiation. A similar effect was observed when IFN was added to differentiated THP-1 cells. Treatment with IFN did not change the steady-state levels of apo E mRNA. Furthermore, in the presence of IFN no increased degradation or increased uptake of extracellular apo E was detected. Pulse-chase experiments indicated that IFN reduced the accumulation of extracellular apo E and increased the degradation of intracellular apo E. The inhibitory effect of IFN on apo E production also was observed in human monocyte-derived macrophages. Thus, our data demonstrated that IFN inhibited macrophage apo E production by posttranslational mechanisms. This represents a previously uncharacterized immunoregulatory interaction and lends further support to a relationship between lipid metabolism and the immune system.

Full text

PDF
2034

Images in this article

2033Image
on p.2033
2033Image
on p.2033
2034Image
on p.2034
2035Image
on p.2035
2035Image
on p.2035
2036Image
on p.2036
2037Image
on p.2037

Selected References

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

  1. Arai K. I., Lee F., Miyajima A., Miyatake S., Arai N., Yokota T. Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem. 1990;59:783–836. doi: 10.1146/annurev.bi.59.070190.004031. [DOI] [PubMed] [Google Scholar]
  2. Auwerx J. H., Deeb S., Brunzell J. D., Peng R., Chait A. Transcriptional activation of the lipoprotein lipase and apolipoprotein E genes accompanies differentiation in some human macrophage-like cell lines. Biochemistry. 1988 Apr 19;27(8):2651–2655. doi: 10.1021/bi00408a003. [DOI] [PubMed] [Google Scholar]
  3. Auwerx J. The human leukemia cell line, THP-1: a multifacetted model for the study of monocyte-macrophage differentiation. Experientia. 1991 Jan 15;47(1):22–31. doi: 10.1007/BF02041244. [DOI] [PubMed] [Google Scholar]
  4. Banka C. L., Black A. S., Dyer C. A., Curtiss L. K. THP-1 cells form foam cells in response to coculture with lipoproteins but not platelets. J Lipid Res. 1991 Jan;32(1):35–43. [PubMed] [Google Scholar]
  5. Basheeruddin K., Rechtoris C., Mazzone T. Transcriptional and post-transcriptional control of apolipoprotein E gene expression in differentiating human monocytes. J Biol Chem. 1992 Jan 15;267(2):1219–1224. [PubMed] [Google Scholar]
  6. Basu S. K., Brown M. S., Ho Y. K., Havel R. J., Goldstein J. L. Mouse macrophages synthesize and secrete a protein resembling apolipoprotein E. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7545–7549. doi: 10.1073/pnas.78.12.7545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Basu S. K., Goldstein J. L., Brown M. S. Independent pathways for secretion of cholesterol and apolipoprotein E by macrophages. Science. 1983 Feb 18;219(4586):871–873. doi: 10.1126/science.6823554. [DOI] [PubMed] [Google Scholar]
  8. Borchardt R. A., Davis R. A. Intrahepatic assembly of very low density lipoproteins. Rate of transport out of the endoplasmic reticulum determines rate of secretion. J Biol Chem. 1987 Dec 5;262(34):16394–16402. [PubMed] [Google Scholar]
  9. Brand K., Fowler B. J., Edgington T. S., Mackman N. Tissue factor mRNA in THP-1 monocytic cells is regulated at both transcriptional and posttranscriptional levels in response to lipopolysaccharide. Mol Cell Biol. 1991 Sep;11(9):4732–4738. doi: 10.1128/mcb.11.9.4732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Breslow J. L., McPherson J., Nussbaum A. L., Williams H. W., Lofquist-Kahl F., Karathanasis S. K., Zannis V. I. Identification and DNA sequence of a human apolipoprotein E cDNA clone. J Biol Chem. 1982 Dec 25;257(24):14639–14641. [PubMed] [Google Scholar]
  11. 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]
  12. Clark S. C., Kamen R. The human hematopoietic colony-stimulating factors. Science. 1987 Jun 5;236(4806):1229–1237. doi: 10.1126/science.3296190. [DOI] [PubMed] [Google Scholar]
  13. Curtiss L. K., Forte T. M., Davis P. A. Cord blood plasma lipoproteins inhibit mitogen-stimulated lymphocyte proliferation. J Immunol. 1984 Sep;133(3):1379–1384. [PubMed] [Google Scholar]
  14. Dixon J. L., Furukawa S., Ginsberg H. N. Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from Hep G2 cells by inhibiting early intracellular degradation of apolipoprotein B. J Biol Chem. 1991 Mar 15;266(8):5080–5086. [PubMed] [Google Scholar]
  15. Dyer C. A., Smith R. S., Curtiss L. K. Only multimers of a synthetic peptide of human apolipoprotein E are biologically active. J Biol Chem. 1991 Aug 15;266(23):15009–15015. [PubMed] [Google Scholar]
  16. Faltynek C. R., Finch L. R., Miller P., Overton W. R. Treatment with recombinant IFN-gamma decreases cell surface CD4 levels on peripheral blood monocytes and on myelomonocyte cell lines. J Immunol. 1989 Jan 15;142(2):500–508. [PubMed] [Google Scholar]
  17. Geng Y. J., Hansson G. K. Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages. J Clin Invest. 1992 Apr;89(4):1322–1330. doi: 10.1172/JCI115718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hansson G. K., Holm J., Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989 Jul;135(1):169–175. [PMC free article] [PubMed] [Google Scholar]
  19. Heidenreich S., Gong J. H., Schmidt A., Nain M., Gemsa D. Macrophage activation by granulocyte/macrophage colony-stimulating factor. Priming for enhanced release of tumor necrosis factor-alpha and prostaglandin E2. J Immunol. 1989 Aug 15;143(4):1198–1205. [PubMed] [Google Scholar]
  20. Jonasson L., Hansson G. K., Bondjers G., Noe L., Etienne J. Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. Biochim Biophys Acta. 1990 Jun 12;1053(1):43–48. doi: 10.1016/0167-4889(90)90024-8. [DOI] [PubMed] [Google Scholar]
  21. Koo C., Wernette-Hammond M. E., Innerarity T. L. Uptake of canine beta-very low density lipoproteins by mouse peritoneal macrophages is mediated by a low density lipoprotein receptor. J Biol Chem. 1986 Aug 25;261(24):11194–11201. [PubMed] [Google Scholar]
  22. Lewis D. B., Wilson C. B. Gamma-interferon: an immunoregulatory lymphokine with immunotherapeutic potential. Pediatr Infect Dis J. 1990 Sep;9(9):642–651. [PubMed] [Google Scholar]
  23. Mahley R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622–630. doi: 10.1126/science.3283935. [DOI] [PubMed] [Google Scholar]
  24. Matsumoto A., Naito M., Itakura H., Ikemoto S., Asaoka H., Hayakawa I., Kanamori H., Aburatani H., Takaku F., Suzuki H. Human macrophage scavenger receptors: primary structure, expression, and localization in atherosclerotic lesions. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9133–9137. doi: 10.1073/pnas.87.23.9133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mazzone T., Basheeruddin K. Dissociated regulation of macrophage LDL receptor and apolipoprotein E gene expression by sterol. J Lipid Res. 1991 Mar;32(3):507–514. [PubMed] [Google Scholar]
  26. Mazzone T., Basheeruddin K., Poulos C. Regulation of macrophage apolipoprotein E gene expression by cholesterol. J Lipid Res. 1989 Jul;30(7):1055–1064. [PubMed] [Google Scholar]
  27. Mazzone T., Gump H., Diller P., Getz G. S. Macrophage free cholesterol content regulates apolipoprotein E synthesis. J Biol Chem. 1987 Aug 25;262(24):11657–11662. [PubMed] [Google Scholar]
  28. Mazzone T., Pustelnikas L., Reardon C. A. Post-translational regulation of macrophage apoprotein E production. J Biol Chem. 1992 Jan 15;267(2):1081–1087. [PubMed] [Google Scholar]
  29. Menju M., Tajima S., Yamamoto A. Expression of the apolipoprotein E gene in a human macrophage-like cell line, THP-1. J Biochem. 1989 Sep;106(3):505–510. doi: 10.1093/oxfordjournals.jbchem.a122882. [DOI] [PubMed] [Google Scholar]
  30. Murray H. W., Rubin B. Y., Masur H., Roberts R. B. Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med. 1984 Apr 5;310(14):883–889. doi: 10.1056/NEJM198404053101404. [DOI] [PubMed] [Google Scholar]
  31. O'Brien K. D., Gordon D., Deeb S., Ferguson M., Chait A. Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques. J Clin Invest. 1992 May;89(5):1544–1550. doi: 10.1172/JCI115747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pepe M. G., Curtiss L. K. Apolipoprotein E is a biologically active constituent of the normal immunoregulatory lipoprotein, LDL-In. J Immunol. 1986 May 15;136(10):3716–3723. [PubMed] [Google Scholar]
  33. Rothman J. H., Raymond C. K., Gilbert T., O'Hara P. J., Stevens T. H. A putative GTP binding protein homologous to interferon-inducible Mx proteins performs an essential function in yeast protein sorting. Cell. 1990 Jun 15;61(6):1063–1074. doi: 10.1016/0092-8674(90)90070-u. [DOI] [PubMed] [Google Scholar]
  34. Salomon R. N., Underwood R., Doyle M. V., Wang A., Libby P. Increased apolipoprotein E and c-fms gene expression without elevated interleukin 1 or 6 mRNA levels indicates selective activation of macrophage functions in advanced human atheroma. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2814–2818. doi: 10.1073/pnas.89.7.2814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sariban E., Imamura K., Luebbers R., Kufe D. Transcriptional and posttranscriptional regulation of tumor necrosis factor gene expression in human monocytes. J Clin Invest. 1988 May;81(5):1506–1510. doi: 10.1172/JCI113482. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sato R., Imanaka T., Takatsuki A., Takano T. Degradation of newly synthesized apolipoprotein B-100 in a pre-Golgi compartment. J Biol Chem. 1990 Jul 15;265(20):11880–11884. [PubMed] [Google Scholar]
  37. Sechler J. M., Malech H. L., White C. J., Gallin J. I. Recombinant human interferon-gamma reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4874–4878. doi: 10.1073/pnas.85.13.4874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sparks J. D., Sparks C. E. Insulin modulation of hepatic synthesis and secretion of apolipoprotein B by rat hepatocytes. J Biol Chem. 1990 May 25;265(15):8854–8862. [PubMed] [Google Scholar]
  39. Takagi Y., Dyer C. A., Curtiss L. K. Platelet-enhanced apolipoprotein E production by human macrophages: a possible role in atherosclerosis. J Lipid Res. 1988 Jul;29(7):859–867. [PubMed] [Google Scholar]
  40. Terkeltaub R. A., Dyer C. A., Martin J., Curtiss L. K. Apolipoprotein (apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils. Characterization of intraarticular apo E and demonstration of apo E binding to urate crystals in vivo. J Clin Invest. 1991 Jan;87(1):20–26. doi: 10.1172/JCI114971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tsuchiya S., Yamabe M., Yamaguchi Y., Kobayashi Y., Konno T., Tada K. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer. 1980 Aug;26(2):171–176. doi: 10.1002/ijc.2910260208. [DOI] [PubMed] [Google Scholar]
  42. Van Lenten B. J., Fogelman A. M., Hokom M. M., Benson L., Haberland M. E., Edwards P. A. Regulation of the uptake and degradation of beta-very low density lipoprotein in human monocyte macrophages. J Biol Chem. 1983 Apr 25;258(8):5151–5157. [PubMed] [Google Scholar]
  43. Virca G. D., Northemann W., Shiels B. R., Widera G., Broome S. Simplified northern blot hybridization using 5% sodium dodecyl sulfate. Biotechniques. 1990 Apr;8(4):370–371. [PubMed] [Google Scholar]
  44. Wakasugi N., Virelizier J. L. Defective IFN-gamma production in the human neonate. I. Dysregulation rather than intrinsic abnormality. J Immunol. 1985 Jan;134(1):167–171. [PubMed] [Google Scholar]
  45. Watanabe Y., Jacob C. O. Regulation of MHC class II antigen expression. Opposing effects of tumor necrosis factor-alpha on IFN-gamma-induced HLA-DR and Ia expression depends on the maturation and differentiation stage of the cell. J Immunol. 1991 Feb 1;146(3):899–905. [PubMed] [Google Scholar]
  46. Werb Z., Chin J. R. Apoprotein E is synthesized and secreted by resident and thioglycollate-elicited macrophages but not by pyran copolymer- or bacillus Calmette-Guerin-activated macrophages. J Exp Med. 1983 Oct 1;158(4):1272–1293. doi: 10.1084/jem.158.4.1272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Werb Z., Chin J. R. Endotoxin suppresses expression of apoprotein E by mouse macrophages in vivo and in culture. A biochemical and genetic study. J Biol Chem. 1983 Sep 10;258(17):10642–10648. [PubMed] [Google Scholar]
  48. Werb Z., Chin J. R. Onset of apoprotein E secretion during differentiation of mouse bone marrow-derived mononuclear phagocytes. J Cell Biol. 1983 Oct;97(4):1113–1118. doi: 10.1083/jcb.97.4.1113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Ye S. Q., Olson L. M., Reardon C. A., Getz G. S. Human plasma lipoproteins regulate apolipoprotein E secretion from a post-Golgi compartment. J Biol Chem. 1992 Oct 25;267(30):21961–21966. [PubMed] [Google Scholar]
  50. Young H. A., Hardy K. J. Interferon-gamma: producer cells, activation stimuli, and molecular genetic regulation. Pharmacol Ther. 1990;45(1):137–151. doi: 10.1016/0163-7258(90)90012-q. [DOI] [PubMed] [Google Scholar]
  51. Zannis V. I., vanderSpek J., Silverman D. Intracellular modifications of human apolipoprotein E. J Biol Chem. 1986 Oct 15;261(29):13415–13421. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES