IL-18 regulates IL-1 beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1

Proinflammatory cytokines, including IL-1 beta and tumor necrosis factor-al pha (TNF-alpha), promote cancer cell adhesion and liver metastases by up-re gulating the expression of vascular cell adhesion molecule-1 (VCAM-1) on he patic 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-conve rting 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-de ficient mice. In vitro, conditioned medium from B16M cells (B16M-CM) induce d the release of TNF-alpha and IL-1 beta from cultures of primary murine HS E. 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 als o increased the number of adhering melanoma cells; however, this was not af fected by IL-1 receptor blockade or TNF neutralization but rather by anti-V CAM-1. These results demonstrate a role for IL-1 beta and IL-18 in the deve lopment of hepatic metastases of B16M in vivo. In vitro, soluble products f rom 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 adhere nce of melanoma cells.