Inflammation Research

, Volume 45, Issue 10, pp 503–507 | Cite as

Modulation of tumor necrosis factor (TNF) receptor expression during monocytic differentiation by glucocorticoids

  • M. Goppelt-Struebe
  • C. O. A. Reiser
  • N. Schneider
  • M. Grell
Original Research Papers


Objective and Design:

Regulation of tumor necrosis factor receptors by glucocorticoids was investigated during phorbol ester-induced monocytic differentiation.

Materials and Treatment:

As model system the human monocytic cell lines U937 and THP-1, which express both types of TNF receptors (TNF-R60 and TNF-R80), were differentiated with tetradecanoyl phorbol-13-acetate (TPA, 5×10−9 M) in the presence or absence of dexamethasone (10−9–10−6 M).


Expression of TNF receptors was determined at the mRNA level by Northern blot analysis and at the protein level by FACS analysis.


During differentiation, TNF-R60 mRNA was down-regulated, whereas TNF-R80 mRNA levels were increased. Dexamethasone had no effect on TNF-R60 mRNA expression but attenuated TNF-R80 mRNA expression in both cell lines. Cell surface expression of TNF-R60 protein remained essentially unchanged during differentiation of THP-1 cells, whereas a rapid down-regulation of TNF-R80 was observed that was followed by a slow recovery. Surface expression of TNF-R80 was not affected by dexamethasone, whereas TNF-R60 expression was reduced by about 25%.


These results indicate differential regulation of the two types of TNF receptors at the mRNA and protein level during monocytic differentiation. Glucocorticoids interfered with mRNA expression of TNF-R80 and protein expression of TNF-R60, but the rather limited effect leaves the question of its functional relevance open. In contrast to other cytokine systems, TNF receptors do not appear to be major targets of glucocorticoid action.

Key words

Glucocorticoids Tumor necrosis factor receptors Monocytic cells 





ribonucleic acid


messenger RNA


ribosomal RNA


human monocytic cell line


tumor necrosis factor α


TNF receptor 55-60kDa


TNF receptor 70-80kDa


tetradecanoyl phorbol-13-acetate


human monocytic cell line


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  1. [1]
    Akahoshi T, Oppenheim JJ, Matsushima K. Induction of high-affinity interleukin 1 receptor on human peripheral blood lymphocytes by glucocorticoid hormones. J Exp Med 1988;167:924–36.CrossRefGoogle Scholar
  2. [2]
    Re F, Muzio M, De Rossi M, Polentarutti N, Giri JG, Mantovani A, et al. The type II “receptor” as a decoy target for interleukin 1 in polymorphonuclear leukocytes: characterization of induction by dexamathasone and ligand binding properties of the released decoy receptor. J Exp Med 1994;179:739–43.CrossRefGoogle Scholar
  3. [3]
    Monick MM, Aksamit TR, Geist LJ, Hunninghake GW, Dexamethasone inhibits IL-1 and TNF activity in human lung fibroblasts without affecting IL-1 or TNF receptors. Am J Physiol 1994;267:L33–8.PubMedGoogle Scholar
  4. [4]
    Ban E, Marquette C, Sarrieau A, Fitzpatrick F, Fillion G, Milon G, et al. Regulation of interleukin-1 receptor expression in mouse brain and pituitary by lipopolysaccharide and glucocorticoids. Neuroendocrinology 1993;58:581–7.CrossRefGoogle Scholar
  5. [5]
    Grell M, Douni E, Wajant H, Löhden M, Clauss M, Maxeiner B, et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell 1995;83:793–802.CrossRefGoogle Scholar
  6. [6]
    Tartaglia LA, Pennica D, Goeddel DV. Ligand passing: The 75-kDa tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDa TNF receptor. J Biol Chem 1996;268:18542–8.Google Scholar
  7. [7]
    Barbara JA, Smith WB, Gamble JR, Van Ostade X, Vandenabeele P, Tavernier J, et al. Dissociation of TNF-alpha cytotoxic and proinflammatory activities by p55 receptor- and p75 receptor-selective TNF-alpha mutants. EMBO J 1994;13:843–50.CrossRefGoogle Scholar
  8. [8]
    Medvedev AE, Sundan A, Espevik T. Involvement of the tumor necrosis factor receptor p75 in mediating cytotoxicity and gene regulating activities. Eur J Immunol 1994;24:2842–9.CrossRefGoogle Scholar
  9. [9]
    Zhang F, zur Hausen A, Hoffmann R, Grewe M, Decker K. Rat liver macrophages express the 55 kDa tumor necrosis factor receptor: modulation by interferon-gamma, lipopolysaccharide and tumor necrosis factor-alpha. Biol Chem Hoppe Seyler 1994;375:249–54.CrossRefGoogle Scholar
  10. [10]
    Kull FC. Reduction in tumor necrosis factor receptor affinity and cytotoxicity by glucocorticoids. Biochem Biophys Res Commun 1988;153:402–9.CrossRefGoogle Scholar
  11. [11]
    Chambaut-Guerin AM, Guerrier M, Thomopoulos P. Regulation by dexamethasone and 1,23-dihydroxyvitamin D3 of the 75 kD-type A tumor necrosis factor receptor surface expression and mRNA level in human U937 cells. Eur Cyt Network 1991;2:355–60.Google Scholar
  12. [12]
    Brockhaus M, Schoenfeld HJ, Schlaeger EJ, 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 USA 1990;87:3127–31.CrossRefGoogle Scholar
  13. [13]
    Greenblatt MS, Elias L. The type B receptor for tumor necrosis factor-alpha mediates DNA fragmentation in HL-60 and U937 cells and differentiation in HL-60 cells. J Lipid Mediat Cell Signal 1992;80:1339–46.Google Scholar
  14. [14]
    Higuchi M, Aggarwal BB. Okadaic acid induces down-modulation and shedding of tumor necrosis factor receptors. Comparison with another tumor promoter, phorbol ester. J Biol Chem 1993;268:5624–31.PubMedGoogle Scholar
  15. [15]
    Thoma B, Grell M, Scheurich P, Pfizenmaier K. Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J Exp Med 1990;172:1019–23.CrossRefGoogle Scholar
  16. [16]
    Moosmayer D, Dinkel A, Gerlach E, Hessabi B, Grell M, Pfizenmaier K, et al. Coexpression of the human TNF receptors TR60 and TR80 in insect cells: analysis of receptor complex formation. Lymph Cyt Res 1994;13:295–301.Google Scholar
  17. [17]
    Stroebel M, Goppelt-Struebe M. Signal transduction pathways responsible for serotonin-mediated prostaglandin G/H synthase expression in rat mesangial cells. J Biol Chem 1994;269:22952–7.PubMedGoogle Scholar
  18. [18]
    Himmler A, Maurer-Fogy I, Krönke M, Scheurich P, Pfizenmaier K, Lantz M, et al. Molecular cloning and expression of human and rat tumor necrosis factor receptor chain (p69) and its soluble derivative, tumor necrosis factor-binding protein. DNA Cell Biol 1990;9:705–15.CrossRefGoogle Scholar
  19. [19]
    Hoff T, Spencker T, Emmendoerffer A, Goppelt-Struebe M. Effects of glucocorticoids on the TPA-induced monocytic differentiation. J Leukoc Biol 1992;52:173–82.CrossRefGoogle Scholar
  20. [20]
    Abrink M, Gobl AE, Huang RN, Nilsson K., Hellman L. Human cell lines U937, THP-1 and Mono Mac 6 represent relatively immature cells of the monocyte-macrophage cell lineage. Leukemia 1994;8:1579–84.PubMedGoogle Scholar
  21. [21]
    Liabakk NB, Sundan A, Lien E, Laegreid A, Bombara MP, Ranges G, et al. The release of soluble p55 TNF receptor from U937 cells studied by a new p55 immunoassay. J Immunol Meth 1993;163:145–54.CrossRefGoogle Scholar
  22. [22]
    Higuchi M, Aggarwal BB, P80 form of the human tumor necrosis factor receptor is involved in DNA fragmentation. FEBS Lett 1993;331:252–5.CrossRefGoogle Scholar
  23. [23]
    Aggarwal BB, Graff K, Samal B, Higuchi M, Liao WS. Regulation of two forms of the TNF receptors by phorbol ester and dibutyryl cyclic adenosine 3′, 5′-monophosphate in human histiocytic lymphoma cell line U-937. Lymph Cyt Res 1993;12:149–58.Google Scholar
  24. [24]
    Higuchi M, Aggarwal BB. TNF induces internalization of the p60 receptor and shedding of the p80 receptor. J Immunol 1994;152:3550–8.PubMedGoogle Scholar
  25. [25]
    Bjornberg F, Lantz M, Gullberg U. Metalloproteases and serineproteases are involved in the cleavage of the two tumour necrosis factor (TNF) receptors to soluble forms in the myeloid cell lines U937 and THP-1. Scand J Immunol 1995;42:418–24.CrossRefGoogle Scholar
  26. [26]
    Totpal K, Chaturvedi MM, LaPushin R, Aggarwal BB. Retinoids downregulate both p60 and p80 froms of tumor necrosis factor receptors in human histiocytic lymphoma U-937 cells. J Lipid Mediat Cell Signal 1995;85:3547–55.Google Scholar
  27. [27]
    Hass R, Giese G, Meyer G, Hartmann A, Dork T, Kohler L et al. Differentiation and retrodifferentiation of U937 cells: reversible induction and suppression of intermediate filament protein synthesis. Eur J Cell Biol 1990;51:265–71.PubMedGoogle Scholar
  28. [28]
    Zhang L, Higuchi M, Totpal K, Chaturvedi MM, Aggarwal BB. Staurosporine induces the cell surface expression of both forms of human tumor necrosis factor receptors on myeloid and epithelial cells and modulates ligand-induced cellular response. J Biol Chem 1994;269:10270–9.PubMedGoogle Scholar
  29. [29]
    Chan H, Aggarwal BB. Role of tumor necrosis factor receptors in the activation of nuclear factor kappa B in human histiocytic lymphoma U-937 cells. J Biol Chem 1994;269:31424–9.PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag 1996

Authors and Affiliations

  • M. Goppelt-Struebe
    • 1
  • C. O. A. Reiser
    • 1
  • N. Schneider
    • 1
  • M. Grell
    • 2
  1. 1.Medizinische Klinik IVUniversität Erlangen-NürnbergErlangenGermany
  2. 2.Institut für Zellbiologie und ImmunologieUniversität StuttgartStuttgartGermany

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