Kupffer Cells Suppress Hepatocarcinogenesis and Metastasis in Tumor Orthotopic Implanted Kunming Mice

  • Li, X.Y. (Department of Hepatobiliary surgery, Traditonal Chinese Medicine Hospital of Dianjiang) ;
  • Wang, M.Y. (Department of Hepatobiliary surgery, The Second Affiliated Hospital of Chongqing Medical University) ;
  • Zhang, J.Y. (Department of Hepatobiliary surgery, The Second Affiliated Hospital of Chongqing Medical University) ;
  • Li, J.Z. (Department of Hepatobiliary surgery, The Second Affiliated Hospital of Chongqing Medical University) ;
  • Gong, J.P. (Department of Hepatobiliary surgery, The Second Affiliated Hospital of Chongqing Medical University) ;
  • Zhang, Wei (Department of Hepatobiliary surgery, The Second Affiliated Hospital of Chongqing Medical University)
  • Published : 2013.11.30


In this research, we used $GdCl_3$ (gadolinium chloride) to restrain the function of Kupffer cells and assessed effects on hepatocarcinogenesis and metastasis in the Kunming mouse. A 0.25% $GdCl_3$ solution (10 mg/kg b.w.) was infused via the vena caudalis of each mouse 1 week before inoculation of H22 cells and was continued once per three days. Then we observed the follow indexes 3 weeks after injection of H22 cells: tumor weight, histologic characteristics of tumor tissue by light microscopy, ultramicrostructure of Kupffer cells under the electron microscope, distribution and number of Kupffer cells by histochemical staining, and TNF-${\alpha}$ and IFN-${\gamma}$ levels in blood-serum and liver tissue by ELISA and RT-PCR. MMP-2 protein expression was tested by immunohistochemistry. The $GdCl_3$ pretreatment had no effect on the quantity of Kupffer cells, but clearly restrained their functions, with decrease of TNF-${\alpha}$ and IFN-${\gamma}$ levels and elevation of MMP2. Tumor immunity functions were markedly suppressed and tumor growth was accelerated with appearance of metastasis. Furthermore, survival time of trial mice was shortened.


Kupffer cells;hepatocellular carcinoma;gadolinium chloride;suppressive effects


  1. Ahmedin Jemal, Rebecca Siegel, Michael J Thun, et al (2009). Cancer Statistics. CA Cancer J Clin, 59, 225-49.
  2. Bertolino P, McCaughan GW, Bowen DG (2002). Role of primary intrahepatic T-cell activation in the liver tolerance effect. Immunol Cell Biol, 80, 84-92.
  3. Clynes RA, Towers TL, Presta LG, Ravetch JV (2000). Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med, 6, 443-6.
  4. Greten T F, MannsM P, Korangy F (2006). Immunotherapy of hepatocellular carcinoma. J Hepatol, 45, 6, 868-78.
  5. Husztik E, Lazar G, Parducz A (1980). Electron microscopic study of kupffer-cell phagocytosis blockade induced by gadolinium chloride. Br J Exp Pathol, 61, 624.
  6. Irie H, Shiga J (2005). Pathogenesis of herpes simplex hepatitis in macrophage-depletedmice possible involvement of tumor necrosis factor-alpha and inducible nitric oxide synthase in massive apoptosis. Anat Sci Int, 80, 199-211.
  7. Jemal A, Bray F, Forman D, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  8. Karashi M, Nakashima H, Seki S, et al (2013). Distinct development and functions of resident and recruited liver Kupffer cells/macrophages. J Leukoc Biol. [Epub ahead of print]
  9. Karpoff HM, D’Angelica M, Fong Y, et al (1997). Prevention of hepatic tumor metastases in rat with herpes viral vaccines and gamma-interferon. J Clin Invest, 99, 799-804.
  10. Lee CM, Yeoh GC, Olynyk JK (2003). Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro. Int J Biochem Cell Biol, 36, 481-8.
  11. Li Z, Lin H, Yang S, et al (2002). Murine leptin deficiency alters Kupffer cell production of cytokines that regulate the innate immune system. Gastroenterology, 123, 4, 1304-10.
  12. Liu K, He X, Lei BJ, et al (2003). Pathomorphological study on location and distribution of Kupffer cells in hepatocellular carcinoma. World J Gastroenterol, 9, 1946-9.
  13. Luo Y, Yamada H, O'Donnell MA, et al (2004). Recombinant Mycobacterium bovis bacillus Calmette-Guerin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity. Clin Exp Immunol, 137, 24-34.
  14. Okino T, Egami H, Ogawa M, et al (2005). Distribution and significance of macrophage in hepatocyte cancer. Dig. Surg, 4, 135-8.
  15. Roland CR, Walp L, Stack RM, Flye MW (1994). Outcome of Kupffer cell antigen presentation to a cloned murine Th1 lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma. J Immunol, 153, 5453-64.
  16. Satoh T, Saika T, Thompson TC, et al (2003). Macrophages transduced with an adenoviral vector expressing interleukin-12 suppress tumor growth and metastasis in a preclinical metastatic prostate cancer model. Cancer Res, 63, 7853-60.
  17. Siegel R, Naishadham D, Jemal A (2012). Cancerstatistics. CA Cancer J Clin. 62, 10-29.
  18. Smedsrod B, De Bleser PJ, Geerts A, et al (1994). Cell biology of liver endothelial and kupffer cells. Gut, 35, 1509.
  19. Sturm JW, Magdeburg R, Post S, et al (2003). Influence of TNFA on the formation of liver metastases in a syngenic mouse model. Int J Cancer, 107, 11-21
  20. Teufelhofer O, Parzefall W, Schulte-Hermann R, et al (2005). Superoxide generation from Kupffer cells contributes to hepatocarcinogenesis: studies on NADPH oxidase knockout mice. Carcinogenesis, 26, 319-29.
  21. Wang YY, Lo GH, Lai KH (2003). Increased Serum Concentrations of TNF-$\alpha$ is associated with disease progression and malnutrition in hepatocellular carcinoma. J Chin Med Assoc, 66, 592-7.
  22. Yamada H, Matsumoto S, Matsumoto T, Yamada T, Yamashita U (2000). Enhancing effect of an inhibitor of nitric oxide synthesis on bacillus Calmette-Guerin-induced macrophage cytotoxicity against murine bladder cancer cell ine MBT-2 in vitro. Jpn J Cancer Res, 91, 534-42.