The regulation of mononuclear phagocyte entry into S phase by the colony stimulating factor CSF-1

CSF‐1 is a hemopoietic growth factor that specifically regulates the survival, proliferation, and differentiation of mononuclear phagocytic cells. Populations of adherent bone marrow‐derived macrophages (BMM) devoid of CSF‐1 producing cells were used to study regulation by CSF‐1 of macrophage entry into S phase. More than 95% of BMM possess the CSF‐1 receptor. It was shown that 93–98% of BMM are cycling (S phase 8–9 hr, doubling time 24–28 hr) when cultured in the presence of CSF‐1. BMM incubated with 15% FCS in the absence of CSF‐1 or in the presence of CSF‐1 concentrations inducing survival without proliferation enter a quiescent state. This state is characterized by a reduction in the synthesis of DNA (98%), total protein (35%), ribosomal protein (76%), and histone (96%) compared with the synthetic rate of these components in exponentially growing cells. Addition of CSF‐1 to BMM rendered quiescent by removal of CSF‐1 stimulated entry into S phase with a lag period of ∼12 h. This lag period is reduced to 8 hr in BMM made quiescent at concentrations of CSF‐1 inducing survival without proliferation, an effect which may be related to the expected higher protein content of these cells (Tushinski and Stanley, J. Cell. Physiol., 116:67–75). Neutralization of CSF‐1 by antibody at different times during the lag period indicates that CSF‐1 is required for almost the entire lag period for the entry of any cells into S phase. In BMM rendered quiescent by removal of both serum and CSF‐1, purified CSF‐1 without serum stimulated entry of cells into S phase, whereas serum alone was ineffective. The results are consistent with a primary regulatory role of CSF‐1 in mononuclear phagocyte proliferation, survival, and function.