Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1987 Dec 1;166(6):1788–1797. doi: 10.1084/jem.166.6.1788

Downregulation of tumor necrosis factor (TNF) sensitivity via modulation of TNF binding capacity by protein kinase C activators

PMCID: PMC2188787  PMID: 2824656

Abstract

The regulatory action of activators for protein kinase C on the specific binding capacity for recombinant human tumor necrosis factor alpha (TNF-alpha) was studied on various human cell lines. Phorbol myristate acetate (PMA) and oleyl acetyl glycerol (OAG) both are able to rapidly downregulate TNF-binding capacity of normal and malignant cells derived from various tissues. As PMA treatment did not enhance internalization of TNF-alpha-receptor complexes at 37 degrees C, and since OAG was able to downregulate TNF-binding capacity under conditions where internalization and shedding of receptor protein are prevented, we conclude that protein kinase C controls ligand affinity of the TNF-receptor protein, possibly via direct phosphorylation. Protein kinase C triggered downregulation of TNF-alpha-binding capacity concomitantly resulted in reduction of TNF-alpha sensitivity, as revealed from decreased cytotoxic action of TNF-alpha on L 929 cells and from inhibition of TNF-alpha-mediated enhancement of HLA class II antigen expression in Colo 205 cells. Restoration of TNF-binding capacity upon abrogation of protein kinase C stimulation leads to full recovery of TNF responsiveness, further supporting the close linkage of TNF-receptor expression and TNF sensitivity. These data suggest that regulation of TNF-binding capacity by protein kinase C is one of the cellular control mechanisms of TNF responsiveness.

Full Text

The Full Text of this article is available as a PDF (703.1 KB).

Selected References

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

  1. 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]
  2. Aggarwal B. B. Human lymphotoxin. Methods Enzymol. 1985;116:441–448. doi: 10.1016/s0076-6879(85)16035-0. [DOI] [PubMed] [Google Scholar]
  3. Berkovic D., Bartsch H. H., Scheurich P., Ucer U., Pfizenmaier K. IFN-gamma receptors on human tumor cells: relationship between receptor ligand interactions and induction of IFN-gamma response. Immunobiology. 1986 Sep;172(3-5):243–249. doi: 10.1016/s0171-2985(86)80104-8. [DOI] [PubMed] [Google Scholar]
  4. Cantrell D. A., Smith K. A. The interleukin-2 T-cell system: a new cell growth model. Science. 1984 Jun 22;224(4655):1312–1316. doi: 10.1126/science.6427923. [DOI] [PubMed] [Google Scholar]
  5. Creasey A. A., Yamamoto R., Vitt C. R. A high molecular weight component of the human tumor necrosis factor receptor is associated with cytotoxicity. Proc Natl Acad Sci U S A. 1987 May;84(10):3293–3297. doi: 10.1073/pnas.84.10.3293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Goldstein J. L., Anderson R. G., Brown M. S. Coated pits, coated vesicles, and receptor-mediated endocytosis. Nature. 1979 Jun 21;279(5715):679–685. doi: 10.1038/279679a0. [DOI] [PubMed] [Google Scholar]
  7. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  8. Kull F. C., Jr, Jacobs S., Cuatrecasas P. Cellular receptor for 125I-labeled tumor necrosis factor: specific binding, affinity labeling, and relationship to sensitivity. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5756–5760. doi: 10.1073/pnas.82.17.5756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Le J., Vilcek J. Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest. 1987 Mar;56(3):234–248. [PubMed] [Google Scholar]
  10. Pfizenmaier K., Krönke M., Scheurich P., Nagel G. A. Tumor necrosis factor (TNF) alpha: control of TNF-sensitivity and molecular mechanisms of TNF-mediated growth inhibition. Blut. 1987 Jul;55(1):1–10. doi: 10.1007/BF00319635. [DOI] [PubMed] [Google Scholar]
  11. Pfizenmaier K., Scheurich P., Schlüter C., Krönke M. Tumor necrosis factor enhances HLA-A,B,C and HLA-DR gene expression in human tumor cells. J Immunol. 1987 Feb 1;138(3):975–980. [PubMed] [Google Scholar]
  12. Rubin B. Y., Anderson S. L., Sullivan S. A., Williamson B. D., Carswell E. A., Old L. J. High affinity binding of 125I-labeled human tumor necrosis factor (LuKII) to specific cell surface receptors. J Exp Med. 1985 Sep 1;162(3):1099–1104. doi: 10.1084/jem.162.3.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ruggiero V., Latham K., Baglioni C. Cytostatic and cytotoxic activity of tumor necrosis factor on human cancer cells. J Immunol. 1987 Apr 15;138(8):2711–2717. [PubMed] [Google Scholar]
  14. Scheurich P., Krönke M., Schlüter C., Ucer U., Pfizenmaier K. Noncytocidal mechanisms of action of tumor necrosis factor-alpha on human tumor cells: enhancement of HLA gene expression synergistic with interferon-gamma. Immunobiology. 1986 Sep;172(3-5):291–300. doi: 10.1016/s0171-2985(86)80111-5. [DOI] [PubMed] [Google Scholar]
  15. Scheurich P., Thoma B., Ucer U., Pfizenmaier K. Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J Immunol. 1987 Mar 15;138(6):1786–1790. [PubMed] [Google Scholar]
  16. Scheurich P., Ucer U., Krönke M., Pfizenmaier K. Quantification and characterization of high-affinity membrane receptors for tumor necrosis factor on human leukemic cell lines. Int J Cancer. 1986 Jul 15;38(1):127–133. doi: 10.1002/ijc.2910380120. [DOI] [PubMed] [Google Scholar]
  17. Scheurich P., Ucer U., Wrann M., Pfizenmaier K. Early events during primary activation of T cells: antigen receptor cross-linking and interleukin 1 initiate proliferative response of human T cells. Eur J Immunol. 1985 Nov;15(11):1091–1095. doi: 10.1002/eji.1830151105. [DOI] [PubMed] [Google Scholar]
  18. Scheurich P., Unglaub R., Maxeiner B., Thoma B., Zugmaier G., Pfizenmaier K. Rapid modulation of tumor necrosis factor membrane receptors by activators of protein kinase C. Biochem Biophys Res Commun. 1986 Dec 15;141(2):855–860. doi: 10.1016/s0006-291x(86)80251-0. [DOI] [PubMed] [Google Scholar]
  19. Sibley D. R., Benovic J. L., Caron M. G., Lefkowitz R. J. Regulation of transmembrane signaling by receptor phosphorylation. Cell. 1987 Mar 27;48(6):913–922. doi: 10.1016/0092-8674(87)90700-8. [DOI] [PubMed] [Google Scholar]
  20. Sugarman B. J., Aggarwal B. B., Hass P. E., Figari I. S., Palladino M. A., Jr, Shepard H. M. Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science. 1985 Nov 22;230(4728):943–945. doi: 10.1126/science.3933111. [DOI] [PubMed] [Google Scholar]
  21. Tsujimoto M., Yip Y. K., Vilcek J. Tumor necrosis factor: specific binding and internalization in sensitive and resistant cells. Proc Natl Acad Sci U S A. 1985 Nov;82(22):7626–7630. doi: 10.1073/pnas.82.22.7626. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES