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Biotech / Medical : Vertex Pharmaceuticals (VRTX) -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (385)	1/18/2000 11:47:00 PM
From: Miljenko Zuanic	Respond to of 1169

Vol. 97, Issue 2, 734-739, January 18, 2000 Immunology IL-18 regulates IL-1-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1 Fernando Vidal-Vanaclocha,, Giamila Fantuzzi, Lorea Mendoza, Angela M. Fuentes, Miren J. Anasagasti, Javier Martín, Teresa Carrascal, Patrick Walsh, Leonid L. Reznikov, Soo-Hyun Kim, Daniela Novick§, Menachem Rubinstein§, and Charles A. Dinarello,¶ * School of Medicine and Dentistry, University of the Basque Country, 48940 Vizcaya, Spain; University of Colorado Health Sciences Center, Denver, CO 80262; Biomedical Research and Technological Development Institute, 20009 Gipuzkoa, Spain; and § The Weizmann Institute, 76100 Rehovot, Israel Contributed by Charles A. Dinarello, October 27, 1999 Proinflammatory cytokines, including IL-1 and tumor necrosis factor- (TNF-), promote cancer cell adhesion and liver metastases by up-regulating the expression of vascular cell adhesion molecule-1 (VCAM-1) on hepatic sinusoidal endothelium (HSE). In this study, hepatic metastasis after intrasplenically injected mouse B16 melanoma (B16M) cells was reduced 84-95% in mice with null mutations for either IL-1 or the IL-1-converting enzyme (ICE, caspase-1) compared with wild-type mice. On day 12, 47% of wild-type mice were dead compared with 19% of either IL-1 or ICE-deficient mice. In vitro, conditioned medium from B16M cells (B16M-CM) induced the release of TNF- and IL-1 from cultures of primary murine HSE. The effect of B16M-CM on HSE resulted in increased numbers of B16M cells adhering to HSE, which was completely abrogated by a specific inhibitor of ICE, anti-IL-18 or IL-18-binding protein. Exogenous IL-18 added to HSE also increased the number of adhering melanoma cells; however, this was not affected by IL-1 receptor blockade or TNF neutralization but rather by anti-VCAM-1. These results demonstrate a role for IL-1 and IL-18 in the development of hepatic metastases of B16M in vivo. In vitro, soluble products from B16M cells stimulate HSE to sequentially release TNF-, IL-1, and IL-18. The IL-18 cytokine increases expression of VCAM-1 and the adherence of melanoma cells.