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^.