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. 1989 Sep 1;170(3):947–958. doi: 10.1084/jem.170.3.947

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

PMCID: PMC2189439  PMID: 2549168

Abstract

We have investigated control mechanisms of TNF receptor expression (TNF- R) in various human tumor cells and normal peripheral blood monocytes. Activators of protein kinase A (PKA) signal transduction pathways were found to enhance TNF-R expression up to sevenfold, whereas in the same cells, IFN-alpha and -gamma receptors remained unaffected. Inhibitors of protein kinases downregulate both constitutive and cAMP-enhanced TNF- R expression. Binding studies revealed an increase in TNF-R numbers without a change in receptor affinity. Both, direct activators of PKA and inhibitors of phosphodiesterase, raising intracellular levels of cAMP, were found to be effective. As activation of PKA does not slow down the degradation rate of TNF-Rs, but rather enhances protein synthesis-dependent reexpression of TNF-Rs after transient PKC-mediated transmodulation and after tryptic digestion of TNF-Rs, it is concluded that PKA stimulates TNF-R synthesis. Maximum TNF-Rs enhancement is reached after 24 h of stimulation and is reversible, suggesting that receptor upregulation is not linked to irreversible steps of cellular differentiation. PKA-mediated enhancement of TNF-R expression was predominantly observed in normal peripheral blood monocytes and tumor cell lines of myeloid origin. As in these typical TNF producer cells, the production of TNF is also controlled by PKA and PKC, a regulatory circuit is proposed, by which these two independent signal pathways antagonistically regulate TNF production and, at the receptor level, TNF sensitivity.

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Selected References

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  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., Kohr W. J., Hass P. E., Moffat B., Spencer S. A., Henzel W. J., Bringman T. S., Nedwin G. E., Goeddel D. V., Harkins R. N. Human tumor necrosis factor. Production, purification, and characterization. J Biol Chem. 1985 Feb 25;260(4):2345–2354. [PubMed] [Google Scholar]
  3. Appleman M. M., Thompson W. J., Russell T. R. Cyclic nucleotide phosphodiesterases. Adv Cyclic Nucleotide Res. 1973;3:65–98. [PubMed] [Google Scholar]
  4. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  5. Beutler B., Krochin N., Milsark I. W., Luedke C., Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  6. Boyd A. W., Metcalf D. Induction of differentiation in HL60 leukaemic cells: a cell cycle dependent all-or-none event. Leuk Res. 1984;8(1):27–43. doi: 10.1016/0145-2126(84)90029-8. [DOI] [PubMed] [Google Scholar]
  7. Collins S. J. The HL-60 promyelocytic leukemia cell line: proliferation, differentiation, and cellular oncogene expression. Blood. 1987 Nov;70(5):1233–1244. [PubMed] [Google Scholar]
  8. Cuturi M. C., Murphy M., Costa-Giomi M. P., Weinmann R., Perussia B., Trinchieri G. Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. J Exp Med. 1987 Jun 1;165(6):1581–1594. doi: 10.1084/jem.165.6.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Durham J. P., Emler C. A., Butcher F. R., Fontana J. A. Calcium-activated, phospholipid-dependent protein kinase activity and protein phosphorylation in HL60 cells induced to differentiate by retinoic acid. FEBS Lett. 1985 Jun 3;185(1):157–161. doi: 10.1016/0014-5793(85)80761-4. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Hensel G., Männel D. N., Pfizenmaier K., Krönke M. Autocrine stimulation of TNF-alpha mRNA expression in HL-60 cells. Lymphokine Res. 1987 Spring;6(2):119–125. [PubMed] [Google Scholar]
  12. Hilz H., Kaukel E. Divergent action mechanism of cAMP and dibutyryl cAMP on cell proliferation and macromolecular synthesis in HeLa S3 cultures. Mol Cell Biochem. 1973 Jun 27;1(2):229–239. doi: 10.1007/BF01659332. [DOI] [PubMed] [Google Scholar]
  13. Katakami Y., Nakao Y., Koizumi T., Katakami N., Ogawa R., Fujita T. Regulation of tumour necrosis factor production by mouse peritoneal macrophages: the role of cellular cyclic AMP. Immunology. 1988 Aug;64(4):719–724. [PMC free article] [PubMed] [Google Scholar]
  14. Krönke M., Hensel G., Schlüter C., Scheurich P., Schütze S., Pfizenmaier K. Tumor necrosis factor and lymphotoxin gene expression in human tumor cell lines. Cancer Res. 1988 Oct 1;48(19):5417–5421. [PubMed] [Google Scholar]
  15. Krönke M., Schlüter C., Pfizenmaier K. Tumor necrosis factor inhibits MYC expression in HL-60 cells at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1987 Jan;84(2):469–473. doi: 10.1073/pnas.84.2.469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McKnight G. S., Hager L., Palmiter R. D. Butyrate and related inhibitors of histone deacetylation block the induction of egg white genes by steroid hormones. Cell. 1980 Nov;22(2 Pt 2):469–477. doi: 10.1016/0092-8674(80)90357-8. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Nophar Y., Holtmann H., Ber R., Wallach D. Dominance of resistance to the cytocidal effect of tumor necrosis factor in heterokaryons formed by fusion of resistant and sensitive cells. J Immunol. 1988 May 15;140(10):3456–3460. [PubMed] [Google Scholar]
  19. Old L. J. Tumour necrosis factor. Polypeptide mediator network. 1987 Mar 26-Apr 1Nature. 326(6111):330–331. doi: 10.1038/326330a0. [DOI] [PubMed] [Google Scholar]
  20. Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. 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]
  24. 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]
  25. Schütze S., Nottrott S., Scheurich P., Krönke M., Pfizenmaier K. Mechanisms of TNF resistance: identification of membrane phosphoproteins associated with a dominant resistant phenotype in lymphoid-myeloid somatic cell hybrids. Mol Biother. 1988;1(2):96–102. [PubMed] [Google Scholar]
  26. Schütze S., Scheurich P., Pfizenmaier K., Krönke M. Tumor necrosis factor signal transduction. Tissue-specific serine phosphorylation of a 26-kDa cytosolic protein. J Biol Chem. 1989 Feb 25;264(6):3562–3567. [PubMed] [Google Scholar]
  27. 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]
  28. 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]
  29. Ucer U., Bartsch H., Scheurich P., Pfizenmaier K. Biological effects of gamma-interferon on human tumor cells: quantity and affinity of cell membrane receptors for gamma-IFN in relation to growth inhibition and induction of HLA-DR expression. Int J Cancer. 1985 Jul 15;36(1):103–108. doi: 10.1002/ijc.2910360116. [DOI] [PubMed] [Google Scholar]
  30. Zhang Y. H., Lin J. X., Yip Y. K., Vilcek J. Enhancement of cAMP levels and of protein kinase activity by tumor necrosis factor and interleukin 1 in human fibroblasts: role in the induction of interleukin 6. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6802–6805. doi: 10.1073/pnas.85.18.6802. [DOI] [PMC free article] [PubMed] [Google Scholar]

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