title: Interleukin 1 (IL-1)-dependent melanoma hepatic metastasis in vivo; increased endothelial adherence by IL-1-induced mannose receptors and growth factor production in vitro.
abstract: BACKGROUND
  The growth of cancer cells in inflammatory tissue is often observed. This can be the result of favorable conditions for endothelial cell adherence and/or increased production of local growth factors.
  
  
  OBJECTIVE
  The role of the proinflammatory cytokine interleukin 1 (IL-1) in the prometastatic and growth-promoting environment of inflammation was studied in vivo, and the mechanism of cytokine action was studied in vitro as well.
  
  
  METHODS
  Systemic inflammation was induced by the intravenous injection of IL-1 beta or lipopolysaccharide (LPS), and the hepatic metastasizing ability of B16 melanoma (B16) cells following intrasplenic injection was studied. IL-1 receptor blockade was accomplished with the use of the IL-1 receptor antagonist (IL-1Ra). In vitro, IL-1Ra was used to assess the mechanism for prometastasis and growth promotion of cultured hepatic sinusoidal endothelium stimulated with LPS.
  
  
  RESULTS
  There was a statistically significant (P < .01) enhancement in the parameters of hepatic metastasis when B16 cells were injected intrasplenically either 4 hours after IL-1 injection or 6 or 12 hours after LPS injection. IL-1Ra pretreatment reduced IL-1-induced enhancement of metastasis by 73%-87% and completely inhibited the augmentation of metastasis following LPS injection. In vitro, the adherence of melanoma cells to LPS-treated endothelium increased nearly twofold but was completely abrogated when IL-1Ra was added before LPS. Similar to melanoma adherence, a 2.5-fold increase (P < .05) in functional mannose receptors was observed with LPS treatment but was prevented by the addition of IL-1Ra did not affect basal mannose-receptor activity in unstimulated epithelium. Mannose-receptor activity and B16 cell adherence significantly correlated (r = .9) with LPS treatment. Conditioned medium from LPS-stimulated epithelium augmented B16 cell proliferation compared with control conditioned medium (P < .01). Production of B16 cell growth factor(s) was markedly reduced (P < .01) when IL-1Ra was added.
  
  
  CONCLUSIONS
  These results demonstrate that systemic inflammation induces an enhancement of melanoma cell metastasis and growth by IL-1-dependent mechanisms in vivo. In vitro, the mechanism(s) is consistent with IL-1-mediated increase in expression of mannose receptors and production of tumor cell growth factor(s) from the endothelium.
  
  
  CONCLUSIONS
  Given the multiple and complex cytokine cascade induced in vivo and in vitro during LPS-induced systemic inflammation, IL-1 plays a strategic role. Since IL-1Ra is without side effects in humans, studies on intraoperative infusion of IL-1Ra during tumor resection may be indicated.
authors.affiliation: Department of Cellular Biology and Morphological Sciences, University of the Basque Country, Leioa, Vizcaya Spain.
authors.forename: F
authors.initials: F
authors.lastname: Vidal-Vanaclocha
authors.forename: A
authors.initials: A
authors.lastname: Alvarez
authors.forename: A
authors.initials: A
authors.lastname: Asumendi
authors.forename: B
authors.initials: B
authors.lastname: Urcelay
authors.forename: P
authors.initials: P
authors.lastname: Tonino
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000166:cytology; D006133:Growth Substances / Q000096:biosynthesis; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000502:physiology*; D037181:Lectins, C-Type; D008070:Lipopolysaccharides / Q000378:metabolism; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D011956:Receptors, Cell Surface / Q000378:metabolism; D012795:Sialoglycoproteins / Q000502:physiology
chemical_list: D006133:Growth Substances; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D012795:Sialoglycoproteins