Characterization of an interleukin 6 cytokine family antagonist protein from a marine sponge, Callyspongia sp.
An inhibitor of IL-6 binding to the human hepatoma line HepG2 and myeloma cell line U266 was identified in a saline extract of the marine sponge, Callyspongia sp. Functional activity, measured through the increase in haptoglobin production by HepG2 cells stimulated with IL-6, could be strongly inhibited by the extract. Similarly, IL-6-induced production of IgM by the B cell line SKW6.4 was substantially reduced. In neither cell line was there evidence of toxicity produced by the extract. Other sponges of the Callyspongia species were found to contain analogous activity. The activity was destroyed by trypsin treatment or boiling of the extract, suggesting that the inhibition is due to a protein. When the binding of IL-6 to its receptor complex was dissected in vitro, inhibition of binding of IL-6 to soluble receptor by the extract was not detected, but binding of the IL-6-sIL-6R complex to soluble gp130 was inhibited in a dose-dependent fashion. This was borne out in cellular assays since the extract inhibited activation of HepG2 cells stimulated with oncostatin M or leukemia inhibitory factor, cytokines which also use gp130 for signal transduction. These results suggest that the Callyspongia extract contains a protein which blocks the interaction of the IL-6 family of cytokines with their signal transduction moiety, gp130. Elucidation of the structure and mode of action of such a protein would be helpful in designing gp130 antagonists to inhibit the functions of this cytokine family, overproduction of which has been associated with cancer and pathologies of autoimmune disease and AIDS.
Peppard
J V
JV
Pharmaceuticals Division, Ciba-Geigy Corporation, Summit, New Jersey 07901, USA.
Loo
P
P
Sills
M A
MA
Munster
D
D
Pomponi
S A
SA
Wright
A E
AE
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry*; D006528:Carcinoma, Hepatocellular; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors; D006242:Haptoglobins / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008113:Liver Neoplasms; D008562:Membrane Glycoproteins / Q000302:isolation & purification* / Q000494:pharmacology*; D011161:Porifera / Q000737:chemistry*; D018123:Receptors, Interleukin / Q000737:chemistry*; D019947:Receptors, Interleukin-6; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D016207:Cytokines; D006242:Haptoglobins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors