Macrophage colony‐stimulating factor‐, granulocyte‐macrophage colony‐stimulating factor‐, or IL‐3‐dependent survival of macrophages, but not proliferation, requires the expression of p21Waf1 through the phosphatidylinositol 3‐kinase/Akt pathway

Abstract

Mouse bone marrow-derived macrophages proliferate in the presence of macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor, or IL-3, but undergo apoptosis in their absence. Inhibition of extracellular signal-regulated kinases (ERK)-1/2 blocks growth factor-dependent proliferation but not survival, indicating that the two processes require independent signaling pathways. Although M-CSF induces the activation of other kinase pathways, such as c-Jun N-terminal kinase, p38, and phosphatidylinositol 3-kinase (PI-3K), these pathways are not required for proliferation. However, PI-3K is the only one necessary for the induction of survival, as demonstrated using the inhibitors LY294002 and Wortmannin. Growth factors also activate Akt kinase and a transient expression of the cdk inhibitor p21^Waf1, which inhibits apoptosis but is not required for proliferation. PI-3K inhibitors also block growth factor-dependent expression of p21^Waf1 and the activation of Akt. Moreover, the survival induced by cyclosporin A or decorin is also dependent on the PI-3K/Akt kinases and p21^Waf1. These findings demonstrate that the induction of p21^Waf1 through the PI-3K/Akt pathway is a general survival response of macrophages. Our results show that growth factors in macrophages use two pathways: one for proliferation, mediated by ERK, and the other for survival, which requires the PI-3K/Akt kinases and p21^Waf1.