title: Interleukin-1 receptor blockade reduces the number and size of murine B16 melanoma hepatic metastases.
abstract: Hepatic metastasis in melanoma is affected by processes of tumor cell adhesion to sinusoidal cells, avoidance of cytotoxic cells, and local growth-promoting activity. A role for interleukin-1 (IL-1) in these events was evaluated in vitro and in vivo by specifically blocking IL-1 receptors using the naturally occurring IL-1 receptor antagonist (IL-1Ra). At 10- and 100-fold molar excess, IL-1Ra reduced the IL-1-mediated adhesion of B16 melanoma cells to cultured hepatic sinusoidal endothelial cells by 60 and 100%, respectively. Conditioned media derived from murine hepatic sinusoidal endothelial cells contain growth-promoting activity for B16 cells, and IL-1 increased its production 2.5-fold (P < 0.01). The addition of IL-1Ra to sinusoidal cells reduced the spontaneous release of the growth-promoting activity by 32% (P < 0.05). In addition, blocking IL-1 receptors on melanoma cells reduced their responsiveness to endothelial-conditioned medium (P < 0.05). A single dose of IL-1Ra (0.5 mg/kg) given to mice i.p. 2 h prior to intrasplenic injection of melanoma cells reduced the number of hepatic metastases by 50% and the metastatic volume by 70% compared to vehicle-injected controls (P < 0.01). When given 2, 4, and 6 days after the injection of tumor cells, IL-1Ra reduced the volume of metastases by 58% (P < 0.01). Fifty % of mice pretreated with 0.5 mg/kg IL-1Ra and given 3 additional doses on days 2, 4, and 6 died after 13.5 +/- 0.4 days compared to 11.3 +/- 0.2 days for controls (P < 0.01). In mice pretreated and given 10 daily doses at 5 mg/kg, there was an 80% reduction in hepatic metastases. Using this regimen, survival was 18.1 +/- 2.4 days in the IL-1Ra group and 11.2 +/- 1.5 in controls (P < 0.001). These studies demonstrate a significant role for IL-1 in implantation and growth of metastatic melanoma in the liver.
authors.affiliation: Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain.
authors.forename: F
authors.initials: F
authors.lastname: Vidal-Vanaclocha
authors.forename: C
authors.initials: C
authors.lastname: Amézaga
authors.forename: A
authors.initials: A
authors.lastname: Asumendi
authors.forename: G
authors.initials: G
authors.lastname: Kaplanski
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D000818:Animals; D053590:Interleukin 1 Receptor Antagonist Protein; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D008297:Male; D008546:Melanoma, Experimental / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D012795:Sialoglycoproteins / Q000494:pharmacology*
chemical_list: C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins