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. 1989 Sep;84(3):738–743. doi: 10.1172/JCI114231

Endotoxin induction of tumor necrosis factor is enhanced by acid-labile interferon-alpha in acquired immunodeficiency syndrome.

A S Lau 1, J F Livesey 1
PMCID: PMC329714  PMID: 2503543

Abstract

High levels of an acid-labile IFN-alpha have been demonstrated in the sera of patients with symptomatic HIV infection. IFNs have been shown to enhance the cytotoxic and antiproliferative actions of tumor necrosis factor (TNF), which is a potent mediator of inflammation and sepsis. We show that the acid-labile IFN-alpha present in AIDS sera can induce TNF synthesis and sensitize blood monocytes (BM) to endotoxin stimulation resulting in further synthesis of TNF in vitro. TNF production by BM from patients with HIV infections and normal controls was measured by a cytotoxicity assay on L929 cells using human TNF alpha as a standard. BM from AIDS patients spontaneously produce high levels of TNF and are hypersensitive to endotoxin stimulation, resulting in enhanced synthesis of TNF. In determining the mechanism involved, we demonstrated that treatment of normal BM with AIDS sera results in induction of TNF. Neutralization of the acid-labile IFN-alpha in AIDS sera with polyclonal anti-IFN-alpha antibodies results in diminution of TNF induction. In addition, pretreatment of normal BM with AIDS sera, IFN-alpha, or IFN-gamma renders the cells hypersensitive to endotoxin. Consequently, activation of the TNF system by the acid-labile IFN-alpha contributes to some of the physiological disturbances, such as the wasting syndrome, and to the pathophysiology of sepsis in AIDS patients.

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Selected References

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

  1. Abe S., Gatanaga T., Yamazaki M., Soma G., Mizuno D. Purification of rabbit tumor necrosis factor. FEBS Lett. 1985 Jan 28;180(2):203–206. doi: 10.1016/0014-5793(85)81071-1. [DOI] [PubMed] [Google Scholar]
  2. Aggarwal B. B., Eessalu T. E., Hass P. E. Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature. 1985 Dec 19;318(6047):665–667. doi: 10.1038/318665a0. [DOI] [PubMed] [Google Scholar]
  3. Akagawa K. S., Tokunaga T. Lack of binding of bacterial lipopolysaccharide to mouse lung macrophages and restoration of binding by gamma interferon. J Exp Med. 1985 Nov 1;162(5):1444–1459. doi: 10.1084/jem.162.5.1444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beutler B., Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987 Feb 12;316(7):379–385. doi: 10.1056/NEJM198702123160705. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Candler R. V., Rouse B. T., Moore R. N. Regulation of interleukin 1 production by alpha and beta interferons: evidence for both direct and indirect enhancement. J Interferon Res. 1985 Winter;5(1):179–189. doi: 10.1089/jir.1985.5.179. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Cerami A., Beutler B. The role of cachectin/TNF in endotoxic shock and cachexia. Immunol Today. 1988 Jan;9(1):28–31. doi: 10.1016/0167-5699(88)91353-9. [DOI] [PubMed] [Google Scholar]
  9. DeStefano E., Friedman R. M., Friedman-Kien A. E., Goedert J. J., Henriksen D., Preble O. T., Sonnabend J. A., Vilcek J. Acid-labile human leukocyte interferon in homosexual men with Kaposi's sarcoma and lymphadenopathy. J Infect Dis. 1982 Oct;146(4):451–459. doi: 10.1093/infdis/146.4.451. [DOI] [PubMed] [Google Scholar]
  10. Eyster M. E., Goedert J. J., Poon M. C., Preble O. T. Acid-labile alpha interferon. A possible preclinical marker for the acquired immunodeficiency syndrome in hemophilia. N Engl J Med. 1983 Sep 8;309(10):583–586. doi: 10.1056/NEJM198309083091003. [DOI] [PubMed] [Google Scholar]
  11. Katz Y., Cole F. S., Strunk R. C. Synergism between gamma interferon and lipopolysaccharide for synthesis of factor B, but not C2, in human fibroblasts. J Exp Med. 1988 Jan 1;167(1):1–14. doi: 10.1084/jem.167.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Klebanoff S. J., Vadas M. A., Harlan J. M., Sparks L. H., Gamble J. R., Agosti J. M., Waltersdorph A. M. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986 Jun 1;136(11):4220–4225. [PubMed] [Google Scholar]
  13. Lau A. S., Hannigan G. E., Freedman M. H., Williams B. R. Regulation of interferon receptor expression in human blood lymphocytes in vitro and during interferon therapy. J Clin Invest. 1986 May;77(5):1632–1638. doi: 10.1172/JCI112480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lau A. S., Read S. E., Williams B. R. Downregulation of interferon alpha but not gamma receptor expression in vivo in the acquired immunodeficiency syndrome. J Clin Invest. 1988 Oct;82(4):1415–1421. doi: 10.1172/JCI113746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mathison J. C., Wolfson E., Ulevitch R. J. Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest. 1988 Jun;81(6):1925–1937. doi: 10.1172/JCI113540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nawroth P. P., Stern D. M. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986 Mar 1;163(3):740–745. doi: 10.1084/jem.163.3.740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pace J. L., Russell S. W. Activation of mouse macrophages for tumor cell killing. I. Quantitative analysis of interactions between lymphokine and lipopolysaccharide. J Immunol. 1981 May;126(5):1863–1867. [PubMed] [Google Scholar]
  18. Read S. E., LeBrocq F. J., Williams B. R. Persistent elevation of 2-5A synthetase and prognosis in the AIDS-related complex (ARC). Prog Clin Biol Res. 1985;202:405–413. [PubMed] [Google Scholar]
  19. Read S. E., Williams B. R., Coates R. A., Evans W. K., Fanning M. M., Garvey M. B., Shepherd F. A. Elevated levels of interferon-induced 2'-5' oligoadenylate synthetase in generalized persistent lymphadenopathy and the acquired immunodeficiency syndrome. J Infect Dis. 1985 Sep;152(3):466–472. doi: 10.1093/infdis/152.3.466. [DOI] [PubMed] [Google Scholar]
  20. Ruggiero V., Tavernier J., Fiers W., Baglioni C. Induction of the synthesis of tumor necrosis factor receptors by interferon-gamma. J Immunol. 1986 Apr 1;136(7):2445–2450. [PubMed] [Google Scholar]
  21. Shannon K. M., Ammann A. J. Acquired immune deficiency syndrome in childhood. J Pediatr. 1985 Feb;106(2):332–342. doi: 10.1016/s0022-3476(85)80320-6. [DOI] [PubMed] [Google Scholar]
  22. Stone-Wolff D. S., Yip Y. K., Kelker H. C., Le J., Henriksen-Destefano D., Rubin B. Y., Rinderknecht E., Aggarwal B. B., Vilcek J. Interrelationships of human interferon-gamma with lymphotoxin and monocyte cytotoxin. J Exp Med. 1984 Mar 1;159(3):828–843. doi: 10.1084/jem.159.3.828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  24. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  25. Tsujimoto M., Yokota S., Vilcek J., Weissmann G. Tumor necrosis factor provokes superoxide anion generation from neutrophils. Biochem Biophys Res Commun. 1986 Jun 30;137(3):1094–1100. doi: 10.1016/0006-291x(86)90337-2. [DOI] [PubMed] [Google Scholar]
  26. Williams T. W., Bellanti J. A. In vitro synergism between interferons and human lymphotoxin: enhancement of lymphotoxin-induced target cell killing. J Immunol. 1983 Feb;130(2):518–520. [PubMed] [Google Scholar]
  27. Williams T. W., Granger G. A. Lymphocyte in vitro cytotoxicity: lymphotoxins of several mammalian species. Nature. 1968 Sep 7;219(5158):1076–1077. doi: 10.1038/2191076a0. [DOI] [PubMed] [Google Scholar]
  28. Williamson B. D., Carswell E. A., Rubin B. Y., Prendergast J. S., Old L. J. Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5397–5401. doi: 10.1073/pnas.80.17.5397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wong G. H., Goeddel D. V. Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons. 1986 Oct 30-Nov 5Nature. 323(6091):819–822. doi: 10.1038/323819a0. [DOI] [PubMed] [Google Scholar]

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