Resistance to the anti‐proliferative effect of IL‐1 on human melanoma cell line is associated with endogenous production of IL‐1 and IL‐6

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Abstract
A human melanoma cell line (A375–6) became resistant to the anti‐proliferative effect of human IL‐I after a long period of culture. Two stable resistant sub‐clones were obtained, and the mechanism of the IL‐I resistance was investigated. Resistant cells, but not sensitive cells, appeared to produce constitutiveiy IL‐I activity. The activity was neutralized by anti‐IL‐I a antibody but not by anti‐IL‐I β antibody. Resistant cells expressed IL‐I α but not IL‐Iβ mRNA. Therefore, the resistant cells appeared to produce IL‐β α. mRNA for IL‐I receptor antagonist (IL‐I Ra) was not detected in resistant cells, indicating that the resistance is not attributable to IL‐IRa. These resistant cells were also resistant to the anti‐proliferative effect of human IL‐6, but not to that of human TNF. Resistant cells appeared to produce constitutively IL‐6 more than sensitive cells, and IL‐6 production both in sensitive and in resistant cells was augmented by exogenous IL‐I. Furthermore, constitutive production of IL‐6 in resistant cells was inhibited by IL‐I Ra. Type I IL‐I receptor (IL‐IR) mRNA was expressed equally in resistant and sensitive cells. These data indicate that the resistance is not the result of loss of functional IL‐IR and that IL‐I induces IL‐6 in an autocrine manner. It is, therefore, conceivable that endogenous IL‐I and IL‐6 contribute to IL‐I resistance.