Tumor cells suppress cytokine-induced nitric-oxide (NO) production in cerebral endothelial cells.
Nitric oxide (NO) produced by endothelial cells (EC) has been shown to exert cytotoxic activity on tumor cells. In order to analyze events involved in brain metastasis, the modulation of NO production in rat-brain-derived EC was investigated. NO release was increased by tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1 beta, lipopolysaccharide or forskolin in EC219 cells, a rat-brain-microvessel-derived EC line. Dexamethasone decreased NO release by cytokine-activated EC219 cells. Tumor cells (DHD/K12/PROb, a rat colon-carcinoma cell line) were highly adherent to EC219 cells, and adhesion was not modified by TNF-alpha plus IFN-gamma, or by dexamethasone. Addition of tumor cells or tumor-cell-conditioned medium significantly inhibited NO release induced by any of the stimuli examined, but only if added during the initial phase of endothelial-cell activation. Tumor-derived suppression of NO release was also observed in primary cultures of cerebral EC. NO synthase (NOS) activity in cytosol extracts of the cerebral EC line was Ca(2+)-independent and required both NADPH and tetrahydrobiopterin. NOS activity was increased by TNF-alpha and IFN-gamma, and significantly reduced by tumor-cell-conditioned medium. These results suggest that rat colon-carcinoma cells may have developed a protective mechanism involving the release of (a) soluble factor(s) which inhibit(s) NO production by cerebral EC.
Murata
J
J
Division of Neuropathology, CHUV, University of Lausanne, Switzerland.
Corradin
S B
SB
Janzer
R C
RC
Juillerat-Jeanneret
L
L
D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D001921:Brain / Q000098:blood supply*; D002448:Cell Adhesion; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism*; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009249:NADP / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D051381:Rats; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D001708:Biopterins; D009569:Nitric Oxide; D009249:NADP; D003907:Dexamethasone; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C003402:sapropterin