title: STAT5 induces macrophage differentiation of M1 leukemia cells through activation of IL-6 production mediated by NF-kappaB p65.
abstract: 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, p21(WAF/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-kappaB p65 (RelA) to the promoter region of IL-6. These findings indicate that STAT5A cooperates with Rel/NF-kappaB 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
authors.affiliation: Division of Hematopoietic Factors, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kawashima
authors.forename: K
authors.initials: K
authors.lastname: Murata
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: Y
authors.initials: Y
authors.lastname: Tonozuka
authors.forename: Y
authors.initials: Y
authors.lastname: Minoshima
authors.forename: S
authors.initials: S
authors.lastname: Feng
authors.forename: H
authors.initials: H
authors.lastname: Kumagai
authors.forename: H
authors.initials: H
authors.lastname: Tsuruga
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.forename: S
authors.initials: S
authors.lastname: Asano
authors.forename: T
authors.initials: T
authors.lastname: Nosaka
authors.forename: T
authors.initials: T
authors.lastname: Kitamura
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D019898:Autocrine Communication; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D015470:Leukemia, Myeloid, Acute; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008894:Milk Proteins; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051996:Transcription Factor RelA; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008894:Milk Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D051996:Transcription Factor RelA