IL-6 antisense-mediated growth inhibition of a choriocarcinoma cell line: an intracellular autocrine growth mechanism.
The growth of tumor cells can be regulated by a variety of cytokines. To investigate the pathogenesis of choriocarcinoma and explore a new therapeutic approach for the carcinoma, we examined the role of IL-6 in the growth of a human choriocarcinoma cell line (JEG-3). IL-6 was identified in the supernatant of the cell culture medium by enzyme-linked immunosorbent assay, indicating that this cell secreted IL-6. The mRNAs of IL-6, IL-6 receptor and gP130, the IL-6 signal transducer, in this cell were shown to be present by reverse transcriptase polymerase chain reaction assay and confirmed by Southern blot hybridization and direct sequencing. The addition of hrIL-6 to the cell culture failed to stimulate cell growth. Monoclonal antibodies against IL-6, IL-6 receptor, and gP130 were also unable to inhibit the proliferation of this cell line. The antisense oligonucleotides targeting IL-6 mRNA, however, inhibited both cell growth and IL-6 production. Taken together, these findings indicate that endogenous IL-6 plays an important role in the growth of the JEG-3 cell line, and it exerts its action by an intracellular autocrine growth mechanism. The results also suggest that the therapeutic trials with monoclonal antibodies designed to neutralize IL-6 or block its receptor will likely fail, whereas the antisense oligonucleotides targeted to IL-6 mRNA may have some value for the treatment of choriocarcinoma and other cancers with intracellular autocrine growth fashion mediated by IL-6.
Department of Obstetrics and Gynecology, Tama Nagayama Hospital, Nippon Medical School, Tama City, Tokyo, Japan.
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Kong
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Isozaki
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Sasaki
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002822:Choriocarcinoma / Q000378:metabolism / Q000473:pathology*; D050822:Cytokine Receptor gp130; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics* / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D016376:Oligonucleotides, Antisense; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050822:Cytokine Receptor gp130