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. 1994 Apr;93(4):1661–1669. doi: 10.1172/JCI117148

Functional switching of macrophage responses to tumor necrosis factor-alpha (TNF alpha) by interferons. Implications for the pleiotropic activities of TNF alpha.

F R Lake 1, P W Noble 1, P M Henson 1, D W Riches 1
PMCID: PMC294209  PMID: 7512988

Abstract

Recent work conducted in our laboratory has been directed towards understanding the role of TNF alpha in stimulating the synthesis of two macrophage gene products, namely IGF-1, a growth factor implicated in wound repair and fibrosis, and complement component factor B (Bf), an alternative pathway complement component. The expression of these proteins is induced by hyaluronic acid and poly (I:C), respectively, although TNF alpha plays a requisite role in the expression of both proteins. The objective of this study was to determine the mechanism governing the dichotomy in the expression of IGF-1 and Bf by TNF alpha. First, we questioned if the diversity in IGF-1 and Bf synthesis was regulated at the level of TNF receptor usage. Second, based on earlier findings that IFNs contribute to the initiation of Bf expression, we determined if IFNs modulate the response of macrophages to TNF alpha. Our data show that differences in TNF receptor usage cannot fully explain the dichotomy in the expression of IGF-1 and Bf. However, prior exposure to IFN-beta or IFN-gamma was found to be a dominant factor controlling the expression of these proteins, suppressing IGF-1, and enhancing Bf. These findings indicate that IFNs mediate a functional "switch" in the response of macrophages to TNF alpha and suggest that the pattern of cytokine expression by diverse macrophage stimuli is an important determinant of the eventual responses of macrophages to TNF alpha.

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Selected References

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

  1. Beutler B., Cerami A. Tumor necrosis, cachexia, shock, and inflammation: a common mediator. Annu Rev Biochem. 1988;57:505–518. doi: 10.1146/annurev.bi.57.070188.002445. [DOI] [PubMed] [Google Scholar]
  2. Borm P. J., Palmen N., Engelen J. J., Buurman W. A. Spontaneous and stimulated release of tumor necrosis factor-alpha (TNF) from blood monocytes of miners with coal workers' pneumoconiosis. Am Rev Respir Dis. 1988 Dec;138(6):1589–1594. doi: 10.1164/ajrccm/138.6.1589. [DOI] [PubMed] [Google Scholar]
  3. Brockhaus M., Schoenfeld H. J., Schlaeger E. J., Hunziker W., Lesslauer W., Loetscher H. Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3127–3131. doi: 10.1073/pnas.87.8.3127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen L., Suzuki Y., Wheelock E. F. Interferon-gamma synergizes with tumor necrosis factor and with interleukin 1 and requires the presence of both monokines to induce antitumor cytotoxic activity in macrophages. J Immunol. 1987 Dec 15;139(12):4096–4101. [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Cole F. S., Auerbach H. S., Goldberger G., Colten H. R. Tissue-specific pretranslational regulation of complement production in human mononuclear phagocytes. J Immunol. 1985 Apr;134(4):2610–2616. [PubMed] [Google Scholar]
  7. Engelmann H., Holtmann H., Brakebusch C., Avni Y. S., Sarov I., Nophar Y., Hadas E., Leitner O., Wallach D. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem. 1990 Aug 25;265(24):14497–14504. [PubMed] [Google Scholar]
  8. Engelmann H., Novick D., Wallach D. Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem. 1990 Jan 25;265(3):1531–1536. [PubMed] [Google Scholar]
  9. Espevik T., Brockhaus M., Loetscher H., Nonstad U., Shalaby R. Characterization of binding and biological effects of monoclonal antibodies against a human tumor necrosis factor receptor. J Exp Med. 1990 Feb 1;171(2):415–426. doi: 10.1084/jem.171.2.415. [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". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Fiers W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS Lett. 1991 Jul 22;285(2):199–212. doi: 10.1016/0014-5793(91)80803-b. [DOI] [PubMed] [Google Scholar]
  13. Hibino Y., Kumar C. S., Mariano T. M., Lai D. H., Pestka S. Chimeric interferon-gamma receptors demonstrate that an accessory factor required for activity interacts with the extracellular domain. J Biol Chem. 1992 Feb 25;267(6):3741–3749. [PubMed] [Google Scholar]
  14. Hohmann H. P., Remy R., Brockhaus M., van Loon A. P. Two different cell types have different major receptors for human tumor necrosis factor (TNF alpha). J Biol Chem. 1989 Sep 5;264(25):14927–14934. [PubMed] [Google Scholar]
  15. Hori K., Mihich E., Ehrke M. J. Role of tumor necrosis factor and interleukin 1 in gamma-interferon-promoted activation of mouse tumoricidal macrophages. Cancer Res. 1989 May 15;49(10):2606–2614. [PubMed] [Google Scholar]
  16. Hyde D. M., Giri S. N. Polyinosinic-polycytidylic acid, an interferon inducer, ameliorates bleomycin-induced lung fibrosis in mice. Exp Lung Res. 1990 Sep-Oct;16(5):533–546. doi: 10.3109/01902149009068825. [DOI] [PubMed] [Google Scholar]
  17. Hyde D. M., Henderson T. S., Giri S. N., Tyler N. K., Stovall M. Y. Effect of murine gamma interferon on the cellular responses to bleomycin in mice. Exp Lung Res. 1988;14(5):687–704. doi: 10.3109/01902148809087837. [DOI] [PubMed] [Google Scholar]
  18. Imamura K., Spriggs D., Kufe D. Expression of tumor necrosis factor receptors on human monocytes and internalization of receptor bound ligand. J Immunol. 1987 Nov 1;139(9):2989–2992. [PubMed] [Google Scholar]
  19. Kelley J. Cytokines of the lung. Am Rev Respir Dis. 1990 Mar;141(3):765–788. doi: 10.1164/ajrccm/141.3.765. [DOI] [PubMed] [Google Scholar]
  20. Kim J. W., Wierda W. G., Kim Y. B. Immobilized IgG immune complex induces secretion of tumor necrosis factor-alpha by porcine alveolar macrophages. Am J Respir Cell Mol Biol. 1991 Sep;5(3):249–255. doi: 10.1165/ajrcmb/5.3.249. [DOI] [PubMed] [Google Scholar]
  21. Kirstein M., Aston C., Hintz R., Vlassara H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J Clin Invest. 1992 Aug;90(2):439–446. doi: 10.1172/JCI115879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lake F. R., Dempsey E. C., Spahn J. D., Riches D. W. Involvement of protein kinase C in macrophage activation by poly(I.C). Am J Physiol. 1994 Jan;266(1 Pt 1):C134–C142. doi: 10.1152/ajpcell.1994.266.1.C134. [DOI] [PubMed] [Google Scholar]
  23. Lewis M., Tartaglia L. A., Lee A., Bennett G. L., Rice G. C., Wong G. H., Chen E. Y., Goeddel D. V. Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2830–2834. doi: 10.1073/pnas.88.7.2830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Loetscher H., Pan Y. C., Lahm H. W., Gentz R., Brockhaus M., Tabuchi H., Lesslauer W. Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor. Cell. 1990 Apr 20;61(2):351–359. doi: 10.1016/0092-8674(90)90815-v. [DOI] [PubMed] [Google Scholar]
  25. Mace K. F., Ehrke M. J., Hori K., Maccubbin D. L., Mihich E. Role of tumor necrosis factor in macrophage activation and tumoricidal activity. Cancer Res. 1988 Oct 1;48(19):5427–5432. [PubMed] [Google Scholar]
  26. Michishita M., Yoshida Y., Uchino H., Nagata K. Induction of tumor necrosis factor-alpha and its receptors during differentiation in myeloid leukemic cells along the monocytic pathway. A possible regulatory mechanism for TNF-alpha production. J Biol Chem. 1990 May 25;265(15):8751–8759. [PubMed] [Google Scholar]
  27. Nagaoka I., Trapnell B. C., Crystal R. G. Regulation of insulin-like growth factor I gene expression in the human macrophage-like cell line U937. J Clin Invest. 1990 Feb;85(2):448–455. doi: 10.1172/JCI114458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nestel F. P., Price K. S., Seemayer T. A., Lapp W. S. Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med. 1992 Feb 1;175(2):405–413. doi: 10.1084/jem.175.2.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Noble P. W., Lake F. R., Henson P. M., Riches D. W. Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages. J Clin Invest. 1993 Jun;91(6):2368–2377. doi: 10.1172/JCI116469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. Piguet P. F., Collart M. A., Grau G. E., Kapanci Y., Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med. 1989 Sep 1;170(3):655–663. doi: 10.1084/jem.170.3.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Piguet P. F., Collart M. A., Grau G. E., Sappino A. P., Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature. 1990 Mar 15;344(6263):245–247. doi: 10.1038/344245a0. [DOI] [PubMed] [Google Scholar]
  33. Prior C., Haslam P. L. Increased levels of serum interferon-gamma in pulmonary sarcoidosis and relationship with response to corticosteroid therapy. Am Rev Respir Dis. 1991 Jan;143(1):53–60. doi: 10.1164/ajrccm/143.1.53. [DOI] [PubMed] [Google Scholar]
  34. Rappolee D. A., Werb Z. mRNA phenotyping for studying gene expression in small numbers of cells: platelet-derived growth factor and other growth factors in wound-derived macrophages. Am J Respir Cell Mol Biol. 1990 Jan;2(1):3–10. doi: 10.1165/ajrcmb/2.1.3. [DOI] [PubMed] [Google Scholar]
  35. Remels L., Fransen L., Huygen K., De Baetselier P. Poly I:C activated macrophages are tumoricidal for TNF-alpha-resistant 3LL tumor cells. J Immunol. 1990 Jun 1;144(11):4477–4486. [PubMed] [Google Scholar]
  36. Riches D. W., Henson P. M. Bacterial lipopolysaccharide suppresses the production of catalytically active lysosomal acid hydrolases in human macrophages. J Cell Biol. 1986 May;102(5):1606–1614. doi: 10.1083/jcb.102.5.1606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Riches D. W., Henson P. M., Remigio L. K., Catterall J. F., Strunk R. C. Differential regulation of gene expression during macrophage activation with a polyribonucleotide. The role of endogenously derived IFN. J Immunol. 1988 Jul 1;141(1):180–188. [PubMed] [Google Scholar]
  38. Riches D. W., Underwood G. A. Expression of interferon-beta during the triggering phase of macrophage cytocidal activation. Evidence for an autocrine/paracrine role in the regulation of this state. J Biol Chem. 1991 Dec 25;266(36):24785–24792. [PubMed] [Google Scholar]
  39. Roberts B. E., Paterson B. M. Efficient translation of tobacco mosaic virus RNA and rabbit globin 9S RNA in a cell-free system from commercial wheat germ. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2330–2334. doi: 10.1073/pnas.70.8.2330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rom W. N., Basset P., Fells G. A., Nukiwa T., Trapnell B. C., Crysal R. G. Alveolar macrophages release an insulin-like growth factor I-type molecule. J Clin Invest. 1988 Nov;82(5):1685–1693. doi: 10.1172/JCI113781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ruff M. R., Gifford G. E. Rabbit tumor necrosis factor: mechanism of action. Infect Immun. 1981 Jan;31(1):380–385. doi: 10.1128/iai.31.1.380-385.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. 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]
  43. Russell S. W., Doe W. F., McIntosh A. T. Functional characterization of a stable, noncytolytic stage of macrophage activation in tumors. J Exp Med. 1977 Dec 1;146(6):1511–1520. doi: 10.1084/jem.146.6.1511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schall T. J., Lewis M., Koller K. J., Lee A., Rice G. C., Wong G. H., Gatanaga T., Granger G. A., Lentz R., Raab H. Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell. 1990 Apr 20;61(2):361–370. doi: 10.1016/0092-8674(90)90816-w. [DOI] [PubMed] [Google Scholar]
  45. Scheurich P., Köbrich G., Pfizenmaier K. Antagonistic control of tumor necrosis factor receptors by protein kinases A and C. Enhancement of TNF receptor synthesis by protein kinase A and transmodulation of receptors by protein kinase C. J Exp Med. 1989 Sep 1;170(3):947–958. doi: 10.1084/jem.170.3.947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schütze S., Berkovic D., Tomsing O., Unger C., Krönke M. Tumor necrosis factor induces rapid production of 1'2'diacylglycerol by a phosphatidylcholine-specific phospholipase C. J Exp Med. 1991 Nov 1;174(5):975–988. doi: 10.1084/jem.174.5.975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Schütze S., Scheurich P., Schlüter C., Ucer U., Pfizenmaier K., Krönke M. Tumor necrosis factor-induced changes of gene expression in U937 cells. Differentiation-dependent plasticity of the responsive state. J Immunol. 1988 May 1;140(9):3000–3005. [PubMed] [Google Scholar]
  48. Shalaby M. R., Laegreid W. W., Ammann A. J., Liggitt H. D. Tumor necrosis factor-alpha-associated uterine endothelial injury in vivo. Influence of dietary fat. Lab Invest. 1989 Nov;61(5):564–570. [PubMed] [Google Scholar]
  49. Smith C. A., Davis T., Anderson D., Solam L., Beckmann M. P., Jerzy R., Dower S. K., Cosman D., Goodwin R. G. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science. 1990 May 25;248(4958):1019–1023. doi: 10.1126/science.2160731. [DOI] [PubMed] [Google Scholar]
  50. Smith R. A., Kirstein M., Fiers W., Baglioni C. Species specificity of human and murine tumor necrosis factor. A comparative study of tumor necrosis factor receptors. J Biol Chem. 1986 Nov 15;261(32):14871–14874. [PubMed] [Google Scholar]
  51. Tartaglia L. A., Goeddel D. V. Two TNF receptors. Immunol Today. 1992 May;13(5):151–153. doi: 10.1016/0167-5699(92)90116-O. [DOI] [PubMed] [Google Scholar]
  52. Tartaglia L. A., Weber R. F., Figari I. S., Reynolds C., Palladino M. A., Jr, Goeddel D. V. The two different receptors for tumor necrosis factor mediate distinct cellular responses. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9292–9296. doi: 10.1073/pnas.88.20.9292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Thomas P. S. Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5201–5205. doi: 10.1073/pnas.77.9.5201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Torres B. A., Johnson H. M. Lipopolysaccharide and polyribonucleotide activation of macrophages: implications for a natural triggering signal in tumor cell killing. Biochem Biophys Res Commun. 1985 Aug 30;131(1):395–401. doi: 10.1016/0006-291x(85)91815-7. [DOI] [PubMed] [Google Scholar]
  55. Tsujimoto M., Feinman R., Vilcek J. Differential effects of type I IFN and IFN-gamma on the binding of tumor necrosis factor to receptors in two human cell lines. J Immunol. 1986 Oct 1;137(7):2272–2276. [PubMed] [Google Scholar]
  56. Underwood G. A., Riches D. W. Transmembrane-mediated changes in [Ca2+] are involved in the signaling pathway leading to macrophage cytocidal differentiation: implications of localized changes in intracellular [Ca2+] and of interferon priming on Ca2+ utilization. Mol Biol Cell. 1992 Mar;3(3):335–347. doi: 10.1091/mbc.3.3.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Vandenabeele P., Declercq W., Vercammen D., Van de Craen M., Grooten J., Loetscher H., Brockhaus M., Lesslauer W., Fiers W. Functional characterization of the human tumor necrosis factor receptor p75 in a transfected rat/mouse T cell hybridoma. J Exp Med. 1992 Oct 1;176(4):1015–1024. doi: 10.1084/jem.176.4.1015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Vassalli P. The pathophysiology of tumor necrosis factors. Annu Rev Immunol. 1992;10:411–452. doi: 10.1146/annurev.iy.10.040192.002211. [DOI] [PubMed] [Google Scholar]
  59. Witsell A. L., Schook L. B. Tumor necrosis factor alpha is an autocrine growth regulator during macrophage differentiation. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4754–4758. doi: 10.1073/pnas.89.10.4754. [DOI] [PMC free article] [PubMed] [Google Scholar]

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