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. 1992 Sep;60(9):3756–3762. doi: 10.1128/iai.60.9.3756-3762.1992

Effects of gamma interferon on release of tumor necrosis factor alpha from lipopolysaccharide-tolerant human monocyte-derived macrophages.

M Matic 1, S R Simon 1
PMCID: PMC257387  PMID: 1500186

Abstract

After an initial stimulation of human monocyte-derived macrophages with bacterial lipopolysaccharide (LPS), which produces substantial release of tumor necrosis factor-alpha (TNF-alpha), a subsequent exposure to LPS results in about an order-of-magnitude reduction in the levels of TNF-alpha released. We have shown that macrophages which have been stimulated with LPS and then maintained in culture without LPS for as long as 2 weeks do not regain their original capacity to secrete TNF-alpha upon a second LPS challenge. After 2 to 4 days in adherent culture, monocyte-derived macrophages which were not pretreated with LPS also experience a measurable decline in their capacity to release TNF-alpha in response to an initial LPS stimulation. When compared with these previously nonstimulated cells, however, the levels of TNF-alpha released by LPS-pretreated cells in response to a second LPS challenge decline by over 90% after 8 to 9 days in culture. Unstimulated cells spontaneously release barely detectable levels of TNF-alpha. In contrast to the release of TNF-alpha, unstimulated cells release significant levels of prostaglandin E2 continuously over time, and these levels are variably increased by no more than a factor of two in response to a single LPS stimulation. Prostaglandin E2 levels released by LPS-pretreated cells in response to a second LPS stimulation are much closer to the levels released by unstimulated cells. We have also demonstrated that gamma interferon (IFN-gamma) enhances TNF-alpha release from LPS-stimulated macrophages but not from phorbol myristate acetate-stimulated cells. Addition of IFN-gamma to macrophages either during the initial stimulation or during a second stimulation with LPS enhances levels of TNF-alpha released after the second LPS challenge. The greatest enhancement is observed when IFN-gamma is added during both exposures to LPS, but addition of IFN-gamma during only the initial LPS stimulation still results in marked enhancement of TNF-alpha release in response to a second stimulation with LPS 24 h later. If an interval of 2 days of culture in medium alone separates the first and second 24-h LPS stimulations, IFN-gamma enhances TNF-alpha release only when it is included during the second LPS exposure, indicating that, unlike the persistence of endotoxin tolerance, enhancement of TNF-alpha release by IFN-gamma is transient.

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Selected References

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  1. Adams D. O., Hamilton T. A. Molecular transductional mechanisms by which IFN gamma and other signals regulate macrophage development. Immunol Rev. 1987 Jun;97:5–27. doi: 10.1111/j.1600-065x.1987.tb00514.x. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
  4. Beutler B., Tkacenko V., Milsark I., Krochin N., Cerami A. Effect of gamma interferon on cachectin expression by mononuclear phagocytes. Reversal of the lpsd (endotoxin resistance) phenotype. J Exp Med. 1986 Nov 1;164(5):1791–1796. doi: 10.1084/jem.164.5.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  6. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Collart M. A., Belin D., Vassalli J. D., de Kossodo S., Vassalli P. Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J Exp Med. 1986 Dec 1;164(6):2113–2118. doi: 10.1084/jem.164.6.2113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Haas J. G., Meyer N., Riethmüller G., Ziegler-Heitbrock H. W. Inhibition of lipopolysaccharide-induced in vitro desensitization by interferon-gamma. Eur J Immunol. 1990 May;20(5):1181–1184. doi: 10.1002/eji.1830200535. [DOI] [PubMed] [Google Scholar]
  9. Haas J. G., Thiel C., Blömer K., Weiss E. H., Riethmüller G., Ziegler-Heitbrock H. W. Downregulation of tumor necrosis factor expression in the human Mono-Mac-6 cell line by lipopolysaccharide. J Leukoc Biol. 1989 Jul;46(1):11–14. doi: 10.1002/jlb.46.1.11. [DOI] [PubMed] [Google Scholar]
  10. Hamilton T. A., Becton D. L., Somers S. D., Gray P. W., Adams D. O. Interferon-gamma modulates protein kinase C activity in murine peritoneal macrophages. J Biol Chem. 1985 Feb 10;260(3):1378–1381. [PubMed] [Google Scholar]
  11. Hamilton T. A., Jansen M. M., Somers S. D., Adams D. O. Effects of bacterial lipopolysaccharide on protein synthesis in murine peritoneal macrophages: relationship to activation for macrophage tumoricidal function. J Cell Physiol. 1986 Jul;128(1):9–17. doi: 10.1002/jcp.1041280103. [DOI] [PubMed] [Google Scholar]
  12. Haslberger A., Sayers T., Reiter H., Chung J., Schütze E. Reduced release of TNF and PCA from macrophages of tolerant mice. Circ Shock. 1988 Oct;26(2):185–192. [PubMed] [Google Scholar]
  13. Kitagawa S., Johnston R. B., Jr Deactivation of the respiratory burst in activated macrophages: evidence for alteration of signal transduction. J Immunol. 1986 Apr 1;136(7):2605–2612. [PubMed] [Google Scholar]
  14. Kornbluth R. S., Gregory S. A., Edgington T. S. Initial characterization of a lymphokine pathway for the immunologic induction of tumor necrosis factor-alpha release from human peripheral blood mononuclear cells. J Immunol. 1988 Sep 15;141(6):2006–2015. [PubMed] [Google Scholar]
  15. Levy G. A., Edgington T. S. Lymphocyte cooperation is required for amplification of macrophage procoagulant activity. J Exp Med. 1980 May 1;151(5):1232–1244. doi: 10.1084/jem.151.5.1232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mathison J. C., Virca G. D., Wolfson E., Tobias P. S., Glaser K., Ulevitch R. J. Adaptation to bacterial lipopolysaccharide controls lipopolysaccharide-induced tumor necrosis factor production in rabbit macrophages. J Clin Invest. 1990 Apr;85(4):1108–1118. doi: 10.1172/JCI114542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Matic M., Simon S. R. Tumor necrosis factor release from lipopolysaccharide-stimulated human monocytes: lipopolysaccharide tolerance in vitro. Cytokine. 1991 Nov;3(6):576–583. doi: 10.1016/1043-4666(91)90484-u. [DOI] [PubMed] [Google Scholar]
  18. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  19. Nedwin G. E., Svedersky L. P., Bringman T. S., Palladino M. A., Jr, Goeddel D. V. Effect of interleukin 2, interferon-gamma, and mitogens on the production of tumor necrosis factors alpha and beta. J Immunol. 1985 Oct;135(4):2492–2497. [PubMed] [Google Scholar]
  20. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Sanchez-Cantu L., Rode H. N., Christou N. V. Endotoxin tolerance is associated with reduced secretion of tumor necrosis factor. Arch Surg. 1989 Dec;124(12):1432–1436. doi: 10.1001/archsurg.1989.01410120082016. [DOI] [PubMed] [Google Scholar]
  23. Somers S. D., Weiel J. E., Hamilton T. A., Adams D. O. Phorbol esters and calcium ionophore can prime murine peritoneal macrophages for tumor cell destruction. J Immunol. 1986 Jun 1;136(11):4199–4205. [PubMed] [Google Scholar]
  24. Weiel J. E., Hamilton T. A., Adams D. O. LPS induces altered phosphate labeling of proteins in murine peritoneal macrophages. J Immunol. 1986 Apr 15;136(8):3012–3018. [PubMed] [Google Scholar]
  25. Wewers M. D., Herzyk D. J. Alveolar macrophages differ from blood monocytes in human IL-1 beta release. Quantitation by enzyme-linked immunoassay. J Immunol. 1989 Sep 1;143(5):1635–1641. [PubMed] [Google Scholar]

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