Oncostatin M binds directly to gp130 and behaves as interleukin-6 antagonist on a cell line expressing gp130 but lacking functional oncostatin M receptors.
Oncostatin M (OM) and interleukin 6 (IL-6) are functionally related cytokines, which trigger similar biological responses because they share gp130 as a common signal transducing transmembrane receptor. While IL-6 recruits gp130 only upon binding to its specific receptor subunit (IL-6R alpha), reconstitution and cross-linking experiments on cell membranes suggest that OM can directly interact with gp130 and that this interaction is necessary but not sufficient to stimulate cells. However, the issue of the direct binding between gp130 and OM, in the absence of any additional membrane component, remained essentially unclarified. In this paper we show that, uniquely among the family of cytokines that transduce through gp130, OM directly binds in vitro with a 10(-8) M affinity sgp130, a soluble form of gp130. Moreover, titration of sgp130 with OM inhibits the formation of a ternary complex comprising IL-6, sIL-6R alpha, and sgp130. These in vitro properties of OM are consistent with the additional finding that on human hepatoma Hep3B cells, which express gp130 but not functional OM receptors, OM does not mimic IL-6 activity, but rather behaves, at high doses, as an IL-6 antagonist.
Sporeno
E
E
Department of Genetics, Istituto di Ricerche di Biologia Molecolare P. Angeletti, Rome, Italy.
Paonessa
G
G
Salvati
A L
AL
Graziani
R
R
Delmastro
P
P
Ciliberto
G
G
Toniatti
C
C
D000818:Animals; D015703:Antigens, CD; D001665:Binding Sites; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology; D018121:Receptors, Cytokine / Q000378:metabolism; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D053677:Receptors, Oncostatin M; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D050822:Cytokine Receptor gp130; D016207:Cytokines; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053683:Oncostatin M; D010455:Peptides; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D053677:Receptors, Oncostatin M; D011994:Recombinant Proteins; D000093242:Interleukin-6 Inhibitors; C494199:IL6ST protein, human; C508351:OSM protein, human