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 inhibi t the growth of cell lines obtained from early but not advanced melano mas. 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 t o IL-6 by IL-6 cDNA transduction. These lines retained the previous on costatin M sensitivity, suggesting that the alpha chain of IL-6 recept or (IL-6R alpha) is involved in the acquisition of resistance, In fact transduced cells lost the ability to bind I-125-IL-6 and to release s oluble IL-6R alpha in culture. Moreover, addition of soluble recombina nt IL-6R alpha were able to restore IL-6 sensitivity in association wi th IL-6 production. On the contrary, naturally IL-6 resistant melanoma cell lines were not inhibited by treatment with recombinant soluble I L-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 resista nce in melanoma cells.