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

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-1 beta 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-1 beta 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-1 beta over IL-1ra was also observed in fresh leukemia cells including monocytic leukemias, i.e., IL-1 beta mRNA 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-1 beta mRNA was stronger than that of IL-1ra even in IL-1ra-positive cases. Apoptotic cell death of monocytes was significantly inhibited by IL-1 beta, 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-1 beta in all cases tested. Cell proliferation was inhibited by either IL-1ra or anti-IL-1 beta 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.