Preferential Production of Interleukin‐1β over Interleukin‐1 Receptor Antagonist Contributes to Proliferation and Suppression of Apoptosis in Leukemic Cells

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Abstract
Normal human monocytes were isolated in a nascent state by centrifugal elutriation and used for the study of interleukin‐1 (IL‐1) and interleukin‐1 receptor antagonist (IL‐1ra) expression. Neither IL‐1β nor IL‐1ra mRNA was present in monocytes just after the isolation, but they were induced simultaneously in response to various stimulants. In contrast, only IL‐1β mRNA was expressed in monocytic leukemia cell line JOSK‐1, while little or no IL‐1ra mRNA was detected even after stimulation. Dominant expression of IL‐1β over IL‐1ra was also observed in fresh leukemia cells including monocytic leukemias, i.e., IL‐1βmRNA was constitutively expressed in 26 out of 36 cases (72.2%), whereas IL‐1ra mRNA was present only in 8 cases (22.2%). The signal intensity of IL‐1βmRNA was stronger than that of IL‐1ra even in IL‐1ra‐positive cases. Apoptotic cell death of monocytes was significantly inhibited by IL‐1β, and it was enhanced by IL‐1ra. In fresh leukemia cells, 3H‐thymidine uptake was generally higher in IL‐1‐producing cases than in IL‐1ra‐producing cases, and was increased by the addition of IL‐1β in all cases tested. Cell proliferation was inhibited by either IL‐1ra or anti‐IL‐1β antibody in IL‐1‐producing cases, while it was enhanced by anti‐IL‐1ra antibody in IL‐1ra‐producing cases. These results suggest that the balance between IL‐1 and IL‐1ra is necessary for homeostasis of the mononuclear phagocytosis system. The imbalance between these two counter‐acting cytokines might contribute to the altered growth and accumulation of leukemic cells.