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Growth Inhibition and Augmentation of Mouse Myeloid Leukemic Cell Line Differentiation by Interleukin 1¹

Department of Microbiology, Institute of Basic Medical Sciences, The University of Tsukuba, Sakura, Niihari, Ibaraki 305 Japan [K. O., T. T., T. H.], and Laboratory of Molecular Immunoregulation, Biological Response Modifiers Program, Division of Cancer Treatment, National Cancer Institute, NIH, Frederick Cancer Research Facility, Frederick, Maryland 21701 [K. M.]

The effect of interleukin 1 (IL 1) on the growth and differentiation of mouse myeloid leukemic cell line (M1) cells into macrophages has been studied. Purified human IL 1ß appeared to be growth inhibitory (maximum, 50%) for M1 cells based on cell counts and [³H]thymidine incorporation. The replication of M1 cells was also inhibited by lipopolysaccharide (LPS), and as little as 1 unit/ml IL 1 augmented the growth inhibition by LPS. Although IL 1 inhibited M1 cell growth, it did not induce cell differentiation by the criteria of either effect on expression of Fc receptors or on phagocytic ability. However, IL 1 augmented M1 cell differentiation in conjunction with LPS. At low doses of LPS, addition of IL 1 induced differentiation even though LPS and IL 1 by themselves did not induce differentiation. Cells treated with IL 1 for 1 day and then with LPS for an additional 2 days showed considerable augmentation of Fc receptor expression, while cells treated with the same stimuli in the reverse sequence exhibited only a low level of differentiation. Cells treated with medium alone followed by LPS showed moderate increase in Fc receptor expression. In addition, exposure of cells to IL 1 for at least 16 h was required for IL 1 augmenting effect. Therefore, IL 1 appeared to primarily influence M1 cells to become more sensitive to LPS. Treatment with both of IL 1 and LPS induced differentiation of a LPS-resistant clone of M1 cells, and IL 1 pretreatment rendered the resistant clone to become responsive to the differentiation inducing effect of LPS. Culture supernatants of M1 cells after stimulation with LPS contained IL 1-like activity by thymocyte comitogenic assays. In addition, mouse recombinant IL 1 appeared to have the same activity as purified human IL 1ß on the growth and differentiation of M1 cells. These results suggest that IL 1 may play an important role in mouse myeloid leukemic cell differentiation by acting as an autostimulating factor. IL 1 has been shown to be growth inhibitory and cytocidal for several tumor cell lines. Our results therefore suggest that the effects of IL 1 may result in the induction of terminal differentiation of some tumor cells.

¹ This work was supported in part by grants from the Ministry of Education, Japan and from the University of Tsukuba project research.

² To whom requests for reprints should be addressed.

Received 9/22/86. Revised 1/30/87. Accepted 2/ 5/87.

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