This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carrascal, M. T. Articles by Dinarello, C. A. Search for Related Content PubMed PubMed Citation Articles by Carrascal, M. T. Articles by Dinarello, C. A.

Interleukin-18 Binding Protein Reduces B16 Melanoma Hepatic Metastasis by Neutralizing Adhesiveness and Growth Factors of Sinusoidal Endothelium¹

Pharmakine Ltd., Zamudio Technology Park, Bizkaia 48170, Spain [M. T. C., L. M., C. S., E. E., N. T., F. V-V.]; Basque Country University School of Medicine and Dentistry, Department of Cellular Biology and Histology, Leioa, Bizkaia 48940, Spain [M. V., F. V-V.]; and University of Colorado Health Sciences Center, Denver, Colorado 80262 [C. A. D.]

We studied the role of endogenous interleukin (IL)-18 in hepatic metastasis by blocking this cytokine using the naturally occurring IL-18 binding protein (IL-18BP). A single i.p. dose of IL-18BP given 30 min before intrasplenic injection of murine B16 melanoma (B16M) cells reduced the number of hepatic metastatic foci by 75% and metastatic volume by 80%. Same treatment reduced the intrahepatic retention of luciferase-transfected B16M by 50% and abolished VCAM-1 up-regulation in the hepatic microvasculature, as assessed by reverse transcription-PCR, Western blot, and immunohistochemistry. Twelve hours after IL-18BP, hepatic sinusoidal endothelium (HSE) cells were isolated, and adhesion of B16M cells to these cultured HSE cells was reduced to the level of vehicle-treated mice. IL-18BP treatment of mice with established micrometastases resulted in a 25% decrease in metastasis number and 40% decrease in metastasis volume, suggesting inhibition of endogenous growth factors. Indeed, the addition of IL-18BP to normal HSE abolished the release of melanoma cell growth factor(s) induced by B16M. IL-18 promoted the in vitro growth of B16M and human melanoma cells, which was IL-1 dependent. These data demonstrate a significant role of endogenous IL-18 on hepatic metastasis by up-regulating melanoma cell adhesion to HSE cells and tumor growth, implicating a possible antimetastatic benefit of neutralizing IL-18.

This article has been cited by other articles:

				Q. Cao, W. Cai, G. Niu, L. He, and X. Chen Multimodality Imaging of IL-18-Binding Protein-Fc Therapy of Experimental Lung Metastasis Clin. Cancer Res., October 1, 2008; 14(19): 6137 - 6145. [Abstract] [Full Text] [PDF]

				J. Kim, Y. Shao, S. Y. Kim, S. Kim, H. K. Song, J. H. Jeon, H. W. Suh, J. W. Chung, S. R. Yoon, Y. S. Kim, et al. Hypoxia-induced IL-18 Increases Hypoxia-inducible Factor-1{alpha} Expression through a Rac1-dependent NF-{kappa}B Pathway Mol. Biol. Cell, February 1, 2008; 19(2): 433 - 444. [Abstract] [Full Text] [PDF]

				P. Auguste, L. Fallavollita, N. Wang, J. Burnier, A. Bikfalvi, and P. Brodt The Host Inflammatory Response Promotes Liver Metastasis by Increasing Tumor Cell Arrest and Extravasation Am. J. Pathol., May 1, 2007; 170(5): 1781 - 1792. [Abstract] [Full Text] [PDF]

				E. C. Lewis and C. A. Dinarello Responses of IL-18- and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor PNAS, November 7, 2006; 103(45): 16852 - 16857. [Abstract] [Full Text] [PDF]

				C. A Dinarello Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process Am. J. Clinical Nutrition, February 1, 2006; 83(2): 447S - 455S. [Abstract] [Full Text] [PDF]

				D. Coradini, S. Zorzet, R. Rossin, I. Scarlata, C. Pellizzaro, C. Turrin, M. Bello, S. Cantoni, A. Speranza, G. Sava, et al. Inhibition of Hepatocellular Carcinomas in vitro and Hepatic Metastases in vivo in Mice by the Histone Deacetylase Inhibitor HA-But Clin. Cancer Res., July 15, 2004; 10(14): 4822 - 4830. [Abstract] [Full Text] [PDF]

				L. Mendoza, M. Valcarcel, T. Carrascal, E. Egilegor, C. Salado, B. K. L. Sim, and F. Vidal-Vanaclocha Inhibition of Cytokine-Induced Microvascular Arrest of Tumor Cells by Recombinant Endostatin Prevents Experimental Hepatic Melanoma Metastasis Cancer Res., January 1, 2004; 64(1): 304 - 310. [Abstract] [Full Text] [PDF]