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.
A human melanoma cell line (A375-6) became resistant to the anti-proliferative effect of human IL-1 after a long period of culture. Two stable resistant sub-clones were obtained, and the mechanism of the IL-1 resistance was investigated. Resistant cells, but not sensitive cells, appeared to produce constitutively IL-1 activity. The activity was neutralized by anti-IL-1 alpha antibody but not by anti-IL-1 beta antibody. Resistant cells expressed IL-1 alpha but not IL-1 beta mRNA. Therefore, the resistant cells appeared to produce IL-1 alpha mRNA for IL-1 receptor antagonist (IL-1Ra) was not detected in resistant cells, indicating that the resistance is not attributable to IL-1Ra. 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-1. Furthermore, constitutive production of IL-6 in resistant cells was inhibited by IL-1Ra. Type I IL-1 receptor (IL-1R) mRNA was expressed equally in resistant and sensitive cells. These data indicate that the resistance is not the result of loss of functional IL-1R and that IL-1 induces IL-6 in an autocrine manner. It is, therefore, conceivable that endogenous IL-1 and IL-6 contribute to IL-1 resistance.
Araki
M
M
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Yano
T
T
Hayashi
H
H
Takii
T
T
Suzuki
K
K
Onozaki
K
K
D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha