IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1.
Proinflammatory cytokines, including IL-1beta 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 B16 melanoma (B16M) cells was reduced 84-95% in mice with null mutations for either IL-1beta or the IL-1beta-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-1beta or ICE-deficient mice. In vitro, conditioned medium from B16M cells (B16M-CM) induced the release of TNF-alpha and IL-1beta 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-1beta 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-1beta, and IL-18. The IL-18 cytokine increases expression of VCAM-1 and the adherence of melanoma cells.
Vidal-Vanaclocha
F
F
School of Medicine and Dentistry, University of the Basque Country, 48940 Vizcaya, Spain.
Fantuzzi
G
G
Mendoza
L
L
Fuentes
A M
AM
Anasagasti
M J
MJ
Martín
J
J
Carrascal
T
T
Walsh
P
P
Reznikov
L L
LL
Kim
S H
SH
Novick
D
D
Rubinstein
M
M
Dinarello
C A
CA
D000818:Animals; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics; D002448:Cell Adhesion; D002455:Cell Division; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007375:Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020382:Interleukin-18 / Q000494:pharmacology / Q000502:physiology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains; D009362:Neoplasm Metastasis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D007375:Interleukin-1; D020382:Interleukin-18; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D020170:Caspase 1