IL-18 regulates IL-1<i>β</i>-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1

Abstract

Proinflammatory cytokines, including IL-1 β and tumor necrosis factor- α (TNF- α ), 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 β or the IL-1 β- 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 β or ICE-deficient mice. In vitro , conditioned medium from B16M cells (B16M-CM) induced the release of TNF- α and IL-1 β 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 β 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- α , IL-1 β , and IL-18. The IL-18 cytokine increases expression of VCAM-1 and the adherence of melanoma cells.

Keywords

Affiliated Institutions

• University of the Basque Country ES
• University of Colorado Health US
• Biomed Research Institute US

Related Publications