Rapid gene repression triggered by interleukin-6 at the onset of monocyte differentiation

To date, the majority of characterized extracellular ligand-induced rapid c hanges in gene expression involve upregulation. Hence, rapid gene repressio n is either less common or less well studied. To study rapid gene repressio n during cytokine-initiated differentiation programs, we used the mRNA subt ractive hybridization technique of representational difference analysis to isolate repressed genes. Cultures of the myeloid leukemia cell line M1 were induced to terminally differentiate by treatment with interleukin-6 (IL-6) . The repressed genes identified in our subtraction products include the ge nes encoding the growth factor receptor Flt3/Flk2/STK-1 (CD135) and the cos timulatory protein CD24 [heat-stable antigen] and the c-myb oncogene. Follo wing 4 h of IL-6 treatment, mRNA levels of these genes are decreased by 45- 65% relative to controls and after 8 h by 65-80%. Lipopolysaccharide also t riggers the repression of these genes. Protein synthesis inhibitors do not block the IL-6-stimulated repression of c-myb, or c-myc, mRNA, yet they do block the repression of flt3 and CD24 mRNA, demonstrating the existence of both protein synthesis-independent and -dependent mechanisms of cytokine-tr iggered rapid gene repression during differentiation. (C) 2000 Academic Pre ss.