期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 97, 期 2, 页码 734-739出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.97.2.734
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资金
- NCI NIH HHS [CA-46934, P30 CA046934] Funding Source: Medline
- NIAID NIH HHS [R56 AI015614, AI-15614, R01 AI015614, AI-2532359] Funding Source: Medline
Proinflammatory cytokines, including IL-1 beta and tumor necrosis factor-alpha (TNF-alpha), 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 816 melanoma (B1684) cells was reduced 84-95% in mice with null mutations for either IL-1 beta or the IL-1 beta-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 beta or ICE-deficient mice. In vitro, conditioned medium from B16M cells (B16M-CM) induced the release of TNF-alpha and IL-1 beta 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 beta 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-alpha, IL-1 beta, and IL-18. The IL-18 cytokine increases expression of VCAM-1 and the adherence of melanoma cells.
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