TNF-? Differentially Regulates Cell Cycle Genes in Promyelocytic and Granulocytic HL-60/S4 Cells.

ABSTRACT: Tumor necrosis factor alpha (TNF-?) is a potent cytokine involved in systemic inflammation and immune modulation. Signaling responses that involve TNF-? are context dependent and capable of stimulating pathways promoting both cell death and survival. TNF-? treatment has been investigated as part of a combined therapy for acute myeloid leukemia due to its modifying effects on all-trans retinoic acid (ATRA) mediated differentiation into granulocytes. To investigate the interaction between cellular differentiation and TNF-?, we performed RNA-sequencing on two forms of the human HL-60/S4 promyelocytic leukemia cell line treated with TNF-?. The ATRA-differentiated granulocytic form of HL-60/S4 cells had an enhanced transcriptional response to TNF-? treatment compared to the undifferentiated promyelocytes. The observed TNF-? responses included differential expression of cell cycle gene sets, which were generally upregulated in TNF-? treated promyelocytes, and downregulated in TNF-? treated granulocytes. This is consistent with TNF-? induced cell cycle repression in granulocytes and cell cycle progression in promyelocytes. Moreover, we found evidence that TNF-? treatment of granulocytes shifts the transcriptome toward that of a macrophage. We conclude that TNF-? treatment promotes a divergent transcriptional program in promyelocytes and granulocytes. TNF-? promotes cell cycle associated gene expression in promyelocytes. In contrast, TNF-? stimulated granulocytes have reduced cell cycle gene expression, and a macrophage-like transcriptional program.

SUBMITTER: Jacobson EC 

PROVIDER: S-EPMC6686940 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature