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Synergistic Regulatory Effects of Interleukin 6 and Interleukin 1 on the Growth and Differentiation of Human and Mouse Myeloid Leukemic Cell Lines¹

Department of Microbiology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305 [K. O., T. Ha.]; Central Research Laboratories, Ajinomoto Co. Ltd., Totsuka, Yokohama 244 [Y. A., A. O.]; Division of Immunology, Institute of Molecular and Cellular Biology, Osaka University, Yamada-Oka, Suita, Osaka 565 [T. Hi., T. K.]; and Department of Cellular Immunology, National Institute of Health, Shinagawa, Tokyo 141 [K. Y., T. T.], Japan

We analyzed the effect of recombinant human interleukin 6 (IL-6), in combination with human recombinant interleukin 1 (IL-1), on the growth and differentiation of several human and mouse myeloid leukemic cell lines, specifically U937, HL-60, M1, and its subclone M1-3b-N, into macrophage-like cells. IL-6 and IL-1 inhibited the growth of U937, M1, and M1-3b-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 M1-3b-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 IL-6 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-1 or IL-1ß. The minimal differentiative effect of IL-1 was not affected by anti-IL-6 antibody. Therefore IL-6 and IL-1 appear to provide distinct signals for differentiation.

¹ This work was supported in part by grants from the Ministry of Education, Japan, from the University of Tsukuba Project Research, and from the Mochida Memorial Foundation for Medical and Pharmacological Research.

² To whom requests for reprints should be addressed.

Received 11/18/88. Revised 3/30/89. Accepted 4/ 5/89.

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