title: Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen-4-mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice.
abstract: The hepatic sinusoidal endothelium (HSE) releases large amounts of reactive oxygen species (ROS) in response to endotoxins and interleukin-1 (IL-1). Such pro-inflammatory mediators have been shown to promote hepatic metastasis. We have investigated the involvement of ROS released by IL-1-stimulated HSE in this promoting effect. Recombinant human interleukin-1 beta (rHuIL-1 beta) (5 micrograms/kg) was intravenously injected into C57BL/6J mice, and the hepatic metastasizing ability of B16 melanoma cells following intrasplenic injection was studied in the presence of ROS scavengers. rHuIL-1 beta-promoted hepatic metastases were significantly (P < .01) reduced by catalase (1 mg/kg) and enhanced by recombinant human superoxide dismutase (rHuSOD) (5 mg/kg). rHuIL-1 beta-stimulated HSE-conditioned medium (HSE-CM) significantly (P < .01) enhanced B16 melanoma cell adhesion to HSE compared with unstimulated HSE-CM, which in turn also significantly (P < .01) increased with melanoma cell adherence compared with basal medium. The addition of catalase completely abrogated proadhesive effects induced by rHuIL-1 beta-stimulated HSE-CM with respect to unstimulated HSE-CM, but did not affect the proadhesive effects induced by unstimulated HSE-CM over basal medium. The rat monoclonal antibody to mouse vascular cell adhesion molecule-1 (VCAM-1) significantly (P < .01) inhibited the enhanced melanoma cell adherence effects of both unstimulated and rHuIL-1 beta-stimulated HSE-CM, indicating that adherence was very late antigen-4 (VLA-4)-mediated. Not surprisingly, the percentage of VLA-4 expressing B16 melanoma cells significantly (P < .05) increased in response to unstimulated (21% of controls) and rHuIL-1 beta-stimulated (32% of controls) HSE-CM. Catalase addition abrogated these effects of rHuIL-1 beta-stimulated-HSE-CM. Melanoma cell damage was observed from the second hour of adhesion to HSE and significantly (P < .01) increased when the cells adhered to rHuIL-1 beta-stimulated HSE. This increase was abrogated by catalase. Cytolysis of the HSE was not observed during melanoma cell adhesion. Neither was the enhancement of B16 melanoma hydrogen peroxide production observed in response to rHuIL-1 beta. Thus, the effects of IL-1 in the liver may consist of a balance between the prometastatic effect of enhanced adherence to the HSE and the antimetastatic effect of H2O2-mediated cytotoxicity. Our results suggest that the enhancement of H2O2 production by the rHuIL-1 beta-stimulated HSE may contribute to the hepatic metastasis progression of ROS-resistant melanoma cells. Results in vitro indicate that this progression is associated with a H2O2-mediated increase in melanoma cell adhesion to HSE.
authors.affiliation: Department of Cell Biology and Morphological Sciences, University of the Basque Country, School of Medicine and Dentistry, Leioa, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Anasagasti
authors.forename: A
authors.initials: A
authors.lastname: Alvarez
authors.forename: J J
authors.initials: JJ
authors.lastname: Martin
authors.forename: L
authors.initials: L
authors.lastname: Mendoza
authors.forename: F
authors.initials: F
authors.lastname: Vidal-Vanaclocha
mesh_terms: D000818:Animals; D002374:Catalase / Q000494:pharmacology; D002448:Cell Adhesion; D016923:Cell Death; D017077:Culture Media, Conditioned; D004727:Endothelium / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000503:physiopathology / Q000556:secondary*; D008297:Male; D008546:Melanoma, Experimental / Q000473:pathology / Q000503:physiopathology / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D016166:Free Radical Scavengers; D039041:Integrin alpha4beta1; D016023:Integrins; D007375:Interleukin-1; D016201:Receptors, Lymphocyte Homing; D006861:Hydrogen Peroxide; D002374:Catalase