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. 1991 Dec 1;174(6):1363–1369. doi: 10.1084/jem.174.6.1363

Sphingosine synergistically stimulates tumor necrosis factor alpha- induced prostaglandin E2 production in human fibroblasts

PMCID: PMC2119053  PMID: 1836009

Abstract

Sphingosine is a biologically active derivative of sphingomyelin. It affects diverse cellular functions and its mechanism(s) of action is poorly defined. Tumor necrosis factor alpha (TNF alpha) has recently been shown to rapidly induce sphingomyelin turnover, implicating this metabolic pathway in TNF alpha signal transduction. Because TNF alpha is known to induce prostaglandin E2 (PGE2) production in human fibroblasts, we tested the effect of sphingosine on TNF alpha-induced PGE2 production. We found that sphingosine enhanced TNF alpha-induced PGE2 production by as much as 18-fold over TNF alpha alone. Sphingosine appeared to stimulate TNF alpha-induced PGE2 production independent of TNF alpha-mediated interleukin 1 (IL-1) production, because anti-IL-1 antibodies and IL-1 receptor antagonist protein (IRAP) did not inhibit TNF alpha-induced PGE2 production or the stimulatory effect of sphingosine. TNF alpha stimulated PGE2 production to the same degree in normal and protein kinase C (PKC) downregulated cells in the presence and absence of sphingosine, indicating that neither TNF alpha nor sphingosine require active PKC to elicit their respective effects. The sphingosine analogues stearylamine and stearoyl-D-sphingosine had little or no effect on TNF alpha-mediated PGE2 production, supporting a specific role for sphingosine in the activation process. Short-term (1 min) exposure of cells to sphingosine dramatically increased TNF alpha- induced PGE2 production. A potential mechanism by which sphingosine could increase TNF alpha-induced PGE2 production involves enhancement of phospholipase A2 (PLA2) and/or cyclooxygenase (Cox) activity, the rate-limiting enzymes in PGE2 production. We found that both TNF alpha and sphingosine alone enhanced these enzymatic activities, and that sphingosine additively increased the effect of TNF alpha on phospholipase A2 activity. It appears that sphingosine affects TNF alpha-induced PGE2 production via a mechanism that is independent of PKC involvement, and that sphingosine may function as an endogenous second messenger capable of modulating the responsiveness of the cell to external stimuli.

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Selected References

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  1. Ballou L. R., Barker S. C., Postlethwaite A. E., Kang A. H. Sphingosine potentiates IL-1-mediated prostaglandin E2 production in human fibroblasts. J Immunol. 1990 Dec 15;145(12):4245–4251. [PubMed] [Google Scholar]
  2. Ballou L. R., Cheung W. Y. Inhibition of human platelet phospholipase A2 activity by unsaturated fatty acids. Proc Natl Acad Sci U S A. 1985 Jan;82(2):371–375. doi: 10.1073/pnas.82.2.371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ballou L. R., Cheung W. Y. Marked increase of human platelet phospholipase A2 activity in vitro and demonstration of an endogenous inhibitor. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5203–5207. doi: 10.1073/pnas.80.17.5203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ballou L. R., DeWitt L. M., Cheung W. Y. Substrate-specific forms of human platelet phospholipase A2. J Biol Chem. 1986 Mar 5;261(7):3107–3111. [PubMed] [Google Scholar]
  5. Bell R. M. Protein kinase C activation by diacylglycerol second messengers. Cell. 1986 Jun 6;45(5):631–632. doi: 10.1016/0092-8674(86)90774-9. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Beutler B., Mahoney J., Le Trang N., Pekala P., Cerami A. Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med. 1985 May 1;161(5):984–995. doi: 10.1084/jem.161.5.984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brenner D. A., O'Hara M., Angel P., Chojkier M., Karin M. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature. 1989 Feb 16;337(6208):661–663. doi: 10.1038/337661a0. [DOI] [PubMed] [Google Scholar]
  9. Davis R. J., Gironès N., Faucher M. Two alternative mechanisms control the interconversion of functional states of the epidermal growth factor receptor. J Biol Chem. 1988 Apr 15;263(11):5373–5379. [PubMed] [Google Scholar]
  10. Dayer J. M., Beutler B., Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985 Dec 1;162(6):2163–2168. doi: 10.1084/jem.162.6.2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Elias J. A., Gustilo K., Baeder W., Freundlich B. Synergistic stimulation of fibroblast prostaglandin production by recombinant interleukin 1 and tumor necrosis factor. J Immunol. 1987 Jun 1;138(11):3812–3816. [PubMed] [Google Scholar]
  13. Faucher M., Gironès N., Hannun Y. A., Bell R. M., Davis R. J. Regulation of the epidermal growth factor receptor phosphorylation state by sphingosine in A431 human epidermoid carcinoma cells. J Biol Chem. 1988 Apr 15;263(11):5319–5327. [PubMed] [Google Scholar]
  14. Ghosh T. K., Bian J., Gill D. L. Intracellular calcium release mediated by sphingosine derivatives generated in cells. Science. 1990 Jun 29;248(4963):1653–1656. doi: 10.1126/science.2163543. [DOI] [PubMed] [Google Scholar]
  15. Grove D. S., Mastro A. M. Prevention of the TPA-mediated down-regulation of protein kinase C. Biochem Biophys Res Commun. 1988 Feb 29;151(1):94–99. doi: 10.1016/0006-291x(88)90563-3. [DOI] [PubMed] [Google Scholar]
  16. Gupta A. K., Fisher G. J., Elder J. T., Nickoloff B. J., Voorhees J. J. Sphingosine inhibits phorbol ester-induced inflammation, ornithine decarboxylase activity, and activation of protein kinase C in mouse skin. J Invest Dermatol. 1988 Nov;91(5):486–491. doi: 10.1111/1523-1747.ep12476635. [DOI] [PubMed] [Google Scholar]
  17. Hakomori S. Bifunctional role of glycosphingolipids. Modulators for transmembrane signaling and mediators for cellular interactions. J Biol Chem. 1990 Nov 5;265(31):18713–18716. [PubMed] [Google Scholar]
  18. Hall F. L., Fernyhough P., Ishii D. N., Vulliet P. R. Suppression of nerve growth factor-directed neurite outgrowth in PC12 cells by sphingosine, an inhibitor of protein kinase C. J Biol Chem. 1988 Mar 25;263(9):4460–4466. [PubMed] [Google Scholar]
  19. Hanai N., Nores G., Torres-Méndez C. R., Hakomori S. Modified ganglioside as a possible modulator of transmembrane signaling mechanism through growth factor receptors: a preliminary note. Biochem Biophys Res Commun. 1987 Aug 31;147(1):127–134. doi: 10.1016/s0006-291x(87)80096-7. [DOI] [PubMed] [Google Scholar]
  20. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  21. Hannun Y. A., Bell R. M. Functions of sphingolipids and sphingolipid breakdown products in cellular regulation. Science. 1989 Jan 27;243(4890):500–507. doi: 10.1126/science.2643164. [DOI] [PubMed] [Google Scholar]
  22. Hannun Y. A., Loomis C. R., Merrill A. H., Jr, Bell R. M. Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J Biol Chem. 1986 Sep 25;261(27):12604–12609. [PubMed] [Google Scholar]
  23. Hovis J. G., Stumpo D. J., Halsey D. L., Blackshear P. J. Effects of mitogens on ornithine decarboxylase activity and messenger RNA levels in normal and protein kinase C-deficient NIH-3T3 fibroblasts. J Biol Chem. 1986 Aug 5;261(22):10380–10386. [PubMed] [Google Scholar]
  24. Jefferson A. B., Schulman H. Sphingosine inhibits calmodulin-dependent enzymes. J Biol Chem. 1988 Oct 25;263(30):15241–15244. [PubMed] [Google Scholar]
  25. Kim M. Y., Linardic C., Obeid L., Hannun Y. Identification of sphingomyelin turnover as an effector mechanism for the action of tumor necrosis factor alpha and gamma-interferon. Specific role in cell differentiation. J Biol Chem. 1991 Jan 5;266(1):484–489. [PubMed] [Google Scholar]
  26. Kovacs E. J., Radzioch D., Young H. A., Varesio L. Differential inhibition of IL-1 and TNF-alpha mRNA expression by agents which block second messenger pathways in murine macrophages. J Immunol. 1988 Nov 1;141(9):3101–3105. [PubMed] [Google Scholar]
  27. 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]
  28. Malinow R., Madison D. V., Tsien R. W. Persistent protein kinase activity underlying long-term potentiation. Nature. 1988 Oct 27;335(6193):820–824. doi: 10.1038/335820a0. [DOI] [PubMed] [Google Scholar]
  29. Meichle A., Schütze S., Hensel G., Brunsing D., Krönke M. Protein kinase C-independent activation of nuclear factor kappa B by tumor necrosis factor. J Biol Chem. 1990 May 15;265(14):8339–8343. [PubMed] [Google Scholar]
  30. Merrill A. H., Jr, Sereni A. M., Stevens V. L., Hannun Y. A., Bell R. M., Kinkade J. M., Jr Inhibition of phorbol ester-dependent differentiation of human promyelocytic leukemic (HL-60) cells by sphinganine and other long-chain bases. J Biol Chem. 1986 Sep 25;261(27):12610–12615. [PubMed] [Google Scholar]
  31. Merrill A. H., Jr, Stevens V. L. Modulation of protein kinase C and diverse cell functions by sphingosine--a pharmacologically interesting compound linking sphingolipids and signal transduction. Biochim Biophys Acta. 1989 Feb 9;1010(2):131–139. doi: 10.1016/0167-4889(89)90152-3. [DOI] [PubMed] [Google Scholar]
  32. Nakano T., Ohara O., Teraoka H., Arita H. Glucocorticoids suppress group II phospholipase A2 production by blocking mRNA synthesis and post-transcriptional expression. J Biol Chem. 1990 Jul 25;265(21):12745–12748. [PubMed] [Google Scholar]
  33. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984 Apr 19;308(5961):693–698. doi: 10.1038/308693a0. [DOI] [PubMed] [Google Scholar]
  34. Okazaki T., Bielawska A., Bell R. M., Hannun Y. A. Role of ceramide as a lipid mediator of 1 alpha,25-dihydroxyvitamin D3-induced HL-60 cell differentiation. J Biol Chem. 1990 Sep 15;265(26):15823–15831. [PubMed] [Google Scholar]
  35. Postlethwaite A. E., Lachman L. B., Kang A. H. Induction of fibroblast proliferation by interleukin-1 derived from human monocytic leukemia cells. Arthritis Rheum. 1984 Sep;27(9):995–1001. doi: 10.1002/art.1780270905. [DOI] [PubMed] [Google Scholar]
  36. Raz A., Wyche A., Siegel N., Needleman P. Regulation of fibroblast cyclooxygenase synthesis by interleukin-1. J Biol Chem. 1988 Feb 25;263(6):3022–3028. [PubMed] [Google Scholar]
  37. Rodriguez-Pena A., Rozengurt E. Disappearance of Ca2+-sensitive, phospholipid-dependent protein kinase activity in phorbol ester-treated 3T3 cells. Biochem Biophys Res Commun. 1984 May 16;120(3):1053–1059. doi: 10.1016/s0006-291x(84)80213-2. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Schütze S., Nottrott S., Pfizenmaier K., Krönke M. Tumor necrosis factor signal transduction. Cell-type-specific activation and translocation of protein kinase C. J Immunol. 1990 Apr 1;144(7):2604–2608. [PubMed] [Google Scholar]
  40. Tsujimoto M., Feinman R., Kohase M., Vilcek J. Characterization and affinity crosslinking of receptors for tumor necrosis factor on human cells. Arch Biochem Biophys. 1986 Sep;249(2):563–568. doi: 10.1016/0003-9861(86)90034-2. [DOI] [PubMed] [Google Scholar]
  41. Wilson E., Olcott M. C., Bell R. M., Merrill A. H., Jr, Lambeth J. D. Inhibition of the oxidative burst in human neutrophils by sphingoid long-chain bases. Role of protein kinase C in activation of the burst. J Biol Chem. 1986 Sep 25;261(27):12616–12623. [PubMed] [Google Scholar]
  42. Zhang H., Buckley N. E., Gibson K., Spiegel S. Sphingosine stimulates cellular proliferation via a protein kinase C-independent pathway. J Biol Chem. 1990 Jan 5;265(1):76–81. [PubMed] [Google Scholar]
  43. Zhang H., Desai N. N., Murphey J. M., Spiegel S. Increases in phosphatidic acid levels accompany sphingosine-stimulated proliferation of quiescent Swiss 3T3 cells. J Biol Chem. 1990 Dec 5;265(34):21309–21316. [PubMed] [Google Scholar]

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