CHARACTERIZATION OF SOLUBLE GP130 RELEASED BY MELANOMA CELL-LINES - APOLYVALENT ANTAGONIST OF CYTOKINES FROM THE INTERLEUKIN-6 FAMILY

gp130 acts as a common transducing signal chain for all receptors belo nging to the interleukin (IL)-6 receptor family, The IL-6-related cyto kines [IL-6, IL-11, oncostatin M (OSM), leukemia inhibitory factor, ci liary neurotrophic factor, and cardiotrophin] often modulate tumor phe notype and control the proliferation of many tumor cell lines, We demo nstrate that melanoma cell lines release, in vitro and in vivo (when t ransplanted in nude mice), soluble gp130 (sgp130), a potential antagon ist of cytokines from the IL-6 family, Biochemical analysis revealed t hat sgp130 derived from melanoma patients' sera or from culture supern atants of melanoma cell lines is a M-r 104,000 protein that resolved a fter deglycosylation as a M-r 58,000 protein, PCR and Northern blot an alysis only identified one gp130 membrane mRNA, suggesting that the so luble form of gp130 is generated by proteolytic cleavage, OSM reproduc ibly increases sgp130 released by melanoma cell lines, whereas leukemi a inhibitory factor stimulates the production of sgp130 in only one of three cell lines tested, This tumor-derived sgp130 is functional beca use it binds in solution to the IL-6-soluble IL-6 receptor (gp80) comp lex, Recombinant sgp130 inhibits the growth inhibitory activity of the IL-6-soluble IL-6 receptor complex and OSM on some melanoma cell Line s, Therefore, this soluble gp130 represents a natural antagonist of cy tokines from the IL-6 family.