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*Dietary Proteins
The Journal of Immunology, 2001, 167: 3652-3660.
Copyright © 2001 by The American Association of Immunologists

STAT5 Induces Macrophage Differentiation of M1 Leukemia Cells Through Activation of IL-6 Production Mediated by NF-{kappa}B p651

Toshiyuki Kawashima*,§, Ken Murata*, Shizuo Akira{ddagger}, Yukio Tonozuka*, Yukinori Minoshima*, Sizhou Feng*, Hidetoshi Kumagai*, Hiromichi Tsuruga*, Yasuo Ikeda§, Shigetaka Asano{dagger}, Tetsuya Nosaka* and Toshio Kitamura2,*

* Division of Hematopoietic Factors and {dagger} Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; {ddagger} Department of Host Defense, Core Research for Engineering, Science, and Technology of Japan Science and Technology Corporation, Research Institute for Microbial Diseases, Osaka University, Suita, Japan; and § Division of Hematology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan

We recently demonstrated that STAT5 can induce a variety of biological functions in mouse IL-3-dependent Ba/F3 cells; STAT5-induced expression of pim-1, p21WAF/Cip1, and suppressor of cytokine signaling-1/STAT-induced STAT inhibitor-1/Janus kinase binding protein is responsible for induction of proliferation, differentiation, and apoptosis, respectively. In the present study, using a constitutively active STAT5A (STAT5A1*6), we show that STAT5 induces macrophage differentiation of mouse leukemic M1 cells through a distinct mechanism, autocrine production of IL-6. The supernatant of STAT5A1*6-transduced cells contained sufficient concentrations of IL-6 to induce macrophage differentiation of parental M1 cells, and STAT3 was phosphorylated on their tyrosine residues in these cells. Treatment of the cells with anti-IL-6 blocking Abs profoundly inhibited the differentiation. We also found that the STAT5A1*6 transactivated the IL-6 promoter, which was mediated by the enhanced binding of NF-{kappa}B p65 (RelA) to the promoter region of IL-6. These findings indicate that STAT5A cooperates with Rel/NF-{kappa}B to induce production of IL-6, thereby inducing macrophage differentiation of M1 cells in an autocrine manner. In summary, we have shown a novel mechanism by which STAT5 induces its pleiotropic functions. Cytokines




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