STAT5 induces macrophage differentiation of M1 leukemia cells through activation of IL-6 production mediated by NF-kappa B p65

We recently demonstrated that STAT5 can induce a variety of biological func tions 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 pr oliferation, differentiation, and apoptosis, respectively. In the present s tudy, using a constitutively active STAT5A (STAT5A1*6), we show that STAT5 induces macrophage differentiation of mouse leukemic Ml cells through a dis tinct mechanism, autocrine production of IL-6. The supernatant of STAT5A1*6 -transduced cells contained sufficient concentrations of IL-6 to induce mac rophage 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 indu ce production of IL-6, thereby inducing macrophage differentiation of Ml ce lls in an autocrine manner. In summary, we have shown a novel mechanism by which STAT5 induces its pleiotropic functions.