Regulation of c‐kit expression in human myeloid cells

In both murine and human systems the c‐kit ligand, also known as mast cell growth factor (MGF), acts synergistically with several colony stimulating factors, including the granulocyte‐macrophage colony stimulating factor (GM‐CSF) and interleukin 3 (IL‐3), in stimulating the proliferation and differentiation of different types of hematopoietic progenitors. In addition, MGF is also known to enhance the effects of GM‐CSF and IL‐3 on the in vitro proliferative activity of myeloid leukemic cells. MGF synergizes with a number of other cytokines such as GM‐CSF, IL‐3, IL‐2, IL‐4, IL‐6 and IL‐9 in sustaining the proliferation of growth factor dependent M‐07e cells. In order to explore the molecular basis of this synergistic activity and to elucidate the regulatory mechanisms of c‐kit expression, we investigated the effects of GM‐CSF, IL‐3 and MGF on c‐kit mRNA and protein levels in M‐07e cells. GM‐CSF, unlike MGF and IL‐3, induced a transient but significant increase of c‐kit mRNA levels. Moreover, following MGF and GM‐CSF treatment, c‐kit protein expression in M‐07e cells decreased, whereas all the other cytokines tested are unable to modulate c‐kit protein. These data together with the results of protein turnover analysis suggest that MGF and GM‐CSF regulate c‐kit expression at the post‐transcriptional level. In addition, the finding that IL‐3 has no detectable effect on c‐kit expression raises the possibility that GM‐CSF‐induced c‐kit regulation is not mediated by the common signal transducing element: the beta subunit of the IL‐3/GM‐CSF receptor complex.