ACQUIRED-RESISTANCE TO THE ANTIPROLIFERATIVE EFFECT OF INTERLEUKIN-1 AND INTERLEUKIN-6 IS A RECESSIVE PHENOTYPE IN A375 HUMAN-MELANOMA CELLS

The proliferation of human melanoma cell line A375-6 is inhibited by s everal cytokines, including interleukin-1 (IL-1) and interleukin-6 (IL -6). However, during a long period of culture, the cells progressively acquire resistance to IL-1 irrespective of functional IL-1 receptor e xpression. These cells constitutively produce IL-1 alpha and IL-6, and also acquire resistance to IL-6. In order to investigate the mechanis m of the acquired resistance to these cytokines, we performed somatic cell hybridization experiments. Parental cells for the construction of hybrid cells were rendered G418- or hygromycin B-resistant by transfe ction with expression vectors containing drug-resistant genes. Hybridi zation was conducted using IL-1-resistant subclones A375-R8 and R19 an d an IL-1 highly sensitive clone C-2-1, which was originally resistant but became sensitive to IL-1 upon transfection with a human type I IL -1 receptor (IL-1R) expression plasmid. Cells produced by hybridizatio n of resistant cells and C-2-1 cells appeared to be sensitive to IL-1 and IL-6. In contrast, production of IL-1 was augmented in the hybrid cells. These results suggest that resistance to IL-1 and IL-6 is a rec essive phenotype, while production of IL-1 is dominant in melanoma cel ls.