GATA-1 blocks IL-6-induced macrophage differentiation and apoptosis through the sustained expression of cyclin D1 and Bcl-2 in a murine myeloid cell line M1

Cytokines exert pleiotropic effects on target cells in a manner dependent o n the cell type or stage of differentiation. To determine how instinctive c ell properties affect biological effects of cytokine, we introduced an eryt hroid/megakaryocyte lineage-specific transcription factor, GATA-1, into a m urine myeloid cell line MI, which is known to undergo macrophage differenti ation in response to interleukin 6 (IL-6). Overexpression of GATA-1 changed the phenotype of M1 cells from myeloid to megakaryocytic lineage. Furtherm ore, GATA-1 blocked both IL-6-induced macrophage differentiation and apopto sis of M1 cells. Although STAT3 is essential for IL-6-induced macrophage di fferentiation of M1 cells, GATA-1 had little or no effect on tyrosine phosp horylation, DNA binding, and transcriptional activities of STAT3 in Western blot analysis, electropholic mobility shift assay (EMSA), and luciferase a ssays. During IL-6-induced macrophage differentiation of M1 cells, IL-6 dow n-regulated cyclin D1 expression and induced p19(INK4D) expression, reading to reduction in cdk4 activities. In contrast, sustained expression of cycl in Dt and a significantly lesser amount of p19(INK4D) induction were observ ed in IL-6-treated M1 cells overexpressing GATA-1. Furthermore, although bc l-2 expression was severely reduced by IL-6 in M1 cells, it was sustained i n GATA-1-introduced M1 cells during the culture with IL-6, Both IL-6-induce d macrophage differentiation and apoptosis were significantly abrogated by coexpression of cyclin D1 and bcl-2, whereas overexpressions of cyclin D1 o r bcl-2 inhibited only differentiation or apoptosis, respectively. These re sults suggested that GATA-1 may not only reprogram the lineage phenotype of M1 cells but also disrupt the biologic effects of IL-6 through the sustain ed expression of cyclin D1 and bcl-2. (C) 2000 by The American Society of H ematology.