A high level of prostaglandin E2 (PGE2) in the portal vein suppresses liver-associated immunity and promotes liver metastases


Prostaglandin E2 (PGE2) is generally accepted to be an immunosuppressant produced by cancer cells and their surrounding macrophages. Although several investigators have reported detecting high concentrations of PGE2 in the portal veins of patients with colorectal cancer, the relationship between these high concentrations of PGE2 in the portal vein and liver-associated immunity remains unclear. In this study, we attempted to determine if the portal administration of PGE2 suppresses the immune function of the liver in a rat model. Donryu rats were administered PGE2 via the portal vein for 7 days, following which the cytotoxic activity of hepatic sinusoidal lymphocytes (HSL) against natural killer (NK)-sensitive YAC-1 and rat syngeneic AH60C tumor cells was assessed. Purified HSL are spontaneously cytolytic; however, the continuous administration of PGE2 dramatically suppressed the cytotoxic activity of HSLs in a dose-dependent fashion. Flow cytometric analysis showed that the large granular lymphocyte (LGL) fraction, hepatic natural killer (pit) cells, and CD48+ killer/suppressor T cells were mainly reduced in number in the HSLs following PGE2 infusion. In this rat AH60C metastasis model, the continuous administration of PGE2 increased the number and size of metastatic tumor nodules in the liver, suggesting that high concentrations of PGE2 in the portal vein suppress liver-associated immunity and promote the formation of hepatic metastasis.

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  1. 1.

    Honn KV, Bockman RS, Marnett LJ (1981) Prostaglandins and cancer: a review of tumor initiation through tumor metastasis. Prostaglandins 21(5):833–864

    Google Scholar 

  2. 2.

    Lynch NR, Salmon JC (1979) Tumor growth inhibition and potentiation of immunotherapy by indomethacin in mice. J Natl Cancer Inst 62:117–121

    Google Scholar 

  3. 3.

    Bennett A, McDonald AM, Stamford IF, Charlier EM, Simpson JS, Zubro T (1977) Prostaglandins and breast cancer Lancet 1:624–626

    Google Scholar 

  4. 4.

    Balch CM, Dougherty PA, Cloud GA, Tilden AB (1984) Prostaglandin E2-mediated suppression of cellular immunity in colon cancer patients. Surgery 95:71–77

    Google Scholar 

  5. 5.

    Sunouchi K (1990) The role of prostaglandin E2 on liver metastasis of colorectal carcinoma (in Japanese with English abstract). Nihon Shoukaki Geka Gakkai Zasshi (Jpn J Gastroenterol Surg) 23:1220–1231

    Google Scholar 

  6. 6.

    Bouwens L, Jacobs R, Remels L, Wisse E (1989) Natural cytotoxicity of rat hepatic natural killer cells and macrophages against a syngeneic colon adenocarcinoma. Cancer Immunol Immunother 27(2):137–141

    Google Scholar 

  7. 7.

    Okuno K, Takagi H, Nakamura T, Nakamura Y, Iwasa Z, Yasutomi M (1986) Treatment for unresectable hepatoma via hepatic arterial infusion of lymphokine-activated killer cells generated from autologous spleen cells. Cancer 58:1001–1006

    Google Scholar 

  8. 8.

    Malter M, Friedrich E, Süss R (1986) Liver as a tumor cell-killing organ: Kupffer cells and natural killers. Cancer Res 46:3055–3060

    Google Scholar 

  9. 9.

    Goodwin JS, Ceuppens (1983) Regulation of the immune response by prostaglandins. J Clin Immunol 3:295–308

    Google Scholar 

  10. 10.

    Goto T, Herberman RB, Maluish A, Strong DM (1983) Cyclic AMP as a mediator of prostaglandin E-induced suppression of human natural killer activity. J Immunol 130:1350–1355

    Google Scholar 

  11. 11.

    Betz M, Fox BS (1991) Prostaglandin E2 inhibits production of Th1 lymphocytes but not of Th2 lymphocytes. J Immunol 146:108–113

    Google Scholar 

  12. 12.

    Johnkoski JA, Tzung SP, Doerr RJ, Cohen SA (1992) Augmentation of the immune response of the murine liver by levamisole. Am J Surg 163:202–207

    Google Scholar 

  13. 13.

    Kaneda K, Dan C, Wake K (1983) Pit cells as natural killer cells. Biomed Res 4:567–576

    Google Scholar 

  14. 14.

    Gorelik E, Wiltrout RH, Okumura K, Habu S, Herberman RB (1982) Role of NK cells in the control of metastatic spread and growth of tumor cells in mice. Int J Cancer 30:107–112

    Google Scholar 

  15. 15.

    Talmadge J, Meyers K, Prieur D, Starkey J (1980) Role of NK cells in tumor growth and metastasis in beige mice. Nature 284:622–624

    Google Scholar 

  16. 16.

    Hanna N, Fidler I (1981) Relationship between metastatic potential and resistance to natural killer cell-mediated cytotoxicity in three murine tumor systems. J Natl Cancer Inst 66:1183–1190

    Google Scholar 

  17. 17.

    Riccardi C, Pucceti P, Santoni A, Herberman RB (1979) Rapid in vivo assay of mouse NK cell activity. J Natl Cancer Inst 63:1041–1045

    Google Scholar 

  18. 18.

    Barlozzari T, Leonhardt J, Wiltrout RH, Herberman RB, Reynolds CW (1985) Direct evidence for the role of NK cells in the inhibition of experimental tumor metastases. J Immunol 134:2783–2389

    Google Scholar 

  19. 19.

    Wiltrout RH, Herberman RB, Zhang R, Chirigos MA, Ortaldo JR, Green KM, Talmadge JE (1985) Role of organ-associated NK cells in decreased formation of experimental metastases in lung and liver. J Immunol 134:4267–4275

    Google Scholar 

  20. 20.

    Johnkoski JA, Tzung SP, Doerr RJ, Cohen SA (1992) Hepatic metastasis alters the immune function of murine liver nonparenchymal cells. Arch Surg 127:1325–1329

    Google Scholar 

  21. 21.

    Seki S, Abo T, Sugiura K (1991) Reciprocal T-cell responses in the liver and thymus of mice injected with syngeneic tumor cells. Cell Immurol 137:46–60

    Google Scholar 

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Correspondence to Kiyotaka Okuno.

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Okuno, K., Jinnai, H., Lee, Y.S. et al. A high level of prostaglandin E2 (PGE2) in the portal vein suppresses liver-associated immunity and promotes liver metastases. Surg Today 25, 954–958 (1995). https://doi.org/10.1007/BF00312380

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Key Words

  • prostaglandin E2
  • liver-associated immunity
  • liver metastasis