Down-regulation of interleukin 6 receptor alpha chain in interleukin 6 transduced melanoma cells causes selective resistance to interleukin 6 but not to oncostatin M.
The cytokines interleukin 6 (IL-6) and oncostatin M are able to inhibit the growth of cell lines obtained from early but not advanced melanomas. Resistant cell lines have frequently been found to produce IL-6. Acquisition of IL-6 resistance and the relationship between resistance and endogenous IL-6 production are poorly defined phenomena. We have characterized a panel of melanoma cell lines for susceptibility to IL-6 and oncostatin M and have generated lines that acquired resistance to IL-6 by IL-6 cDNA transduction. These lines retained the previous oncostatin M sensitivity, suggesting that the alpha chain of IL-6 receptor (IL-6R alpha) is involved in the acquisition of resistance. In fact transduced cells lost the ability to bind 125I-IL-6 and to release soluble IL-6R alpha in culture. Moreover, addition of soluble recombinant IL-6R alpha were able to restore IL-6 sensitivity in association with IL-6 production. On the contrary, naturally IL-6 resistant melanoma cell lines were not inhibited by treatment with recombinant soluble IL-6R alpha in association with endogenously produced or recombinant IL-6. These results demonstrate that down-regulation of IL-6 receptor is only one of different mechanisms that are responsible of IL-6 resistance in melanoma cells.
Silvani
A
A
Division of Experimental Oncology D, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Ferrari
G
G
Paonessa
G
G
Toniatti
C
C
Parmiani
G
G
Colombo
M P
MP
D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism*; D019947:Receptors, Interleukin-6; D014162:Transfection; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; C508351:OSM protein, human; D010455:Peptides; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D053683:Oncostatin M