Leukemic Cell Lines Myeloid on the Growth and Differentiation of Human and Mouse Synergistic Regulatory Effects of Interleukin 6 and Interleukin

We analyzed the effect of recombinant human ¡nterleukin6 (IL-6), in combination with human recombinant interleukin la (IL-la), on the growth and differentiation of several human and mouse myeloid leukemic cell lines, specifically U937, HL-60, Ml, and its subclone Ml-3b-N, into macrophage-like cells. IL-6 and IL-1 inhibited the growth of U937, Ml, and Ml-3b-N in a dose-dependent manner. Treatment of these cells with both IL-6 and IL-1 resulted in either an additive or a synergistic growth inhibition. IL-6 alone induced moderate differentiation of U937 and MI3b-N, but the combination of IL-6 and IL-1 synergistically augmented this differentiation. In M1, only the combination of IL-1 and IL-6 resulted in differentiation. These two cytokines, whether alone or in combination, did not influence the growth and differentiation of HL-60. Therefore II6 in conjunction with IL-1 can induce differentiation in several human and mouse myeloid leukemic cell lines, although this effect varies with cell type. IL-6 did not stimulate the expression of IL-1 mRNA or IL-1 activity in U937 cells. IL-1 also failed to stimulate IL-6 production. Furthermore, the differentiation of U937 cells induced by IL-6 was not neutralized by antibody against either IL-la or II.-M. The minimal differentiate effect of IL-1 was not affected by anti-IL-6 antibody. Therefore IL-6 and IL-1 appear to provide distinct signals for differen tiation. may play an important role in differentiation of mononucleolar phagocytes. Hirano et al. (14, 15) recently succeeded in the purification and cloning of the complementary DNA for BSF-2 which induces the maturation of human B-cells into immunoglobulinsecreting cells. Based on its amino acid sequence BSF-2 ap peared to be identical to the molecule called IFN-02 (16), hybridoma-plasmacytoma growth factor, (17), and the M, 26,000 protein (18), the production of which could be induced in fibroblasts and monocytes by TNF or IL-1 (16-21). Recep tors for BSF-2 appeared to be expressed in a variety of cell types, including Epstein-Barr virus-transformed B-cell lines, plasma cell lines, an astrocytoma cell line, and myeloid leu kemic cell lines (22). This molecule is now called IL-6 (23, 24). Recently we reported that IL-6 is antiproliferative and induces differentiation of a clone of Ml cells (25). As we have observed that IL-1 and other cytokines, IFN-a,/3, and TNF, synergisti cally induced differentiation of Ml cells (11, 12), in this article we determined whether IL-6 also in synergy with IL-1 induces differentiation of U937 and Ml cells.