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

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.