Pathways regulating hypoxia- and CSF-1-induced macrophage survival.

<p>CSF-1-depleted BMM, which die by apoptosis, were exposed to hypoxia and a “pro-survival” CSF-1 concentration. The working model illustrates the putative signaling pathways that regulate hypoxia- and CSF-1-induced macrophage survival based on inhibitor effects. In the presence of both stimuli, PI3-K inhibitors (wortmannin and LY294002) and the mTOR inhibitor (rapamycin) suppress macrophage survival, whereas the Akt inhibitor (Akt VIII) and the p38 MAPK inhibitor (SB203580) suppress apoptosis. It is proposed that hypoxia may regulate macrophage survival independently of CSF-1 via reactive oxygen species (ROS)-mediated NF-κB activation. Hypoxia may also modulate CSF-1-mediated macrophage survival/apoptosis again via ROS, which antagonize the phosphatases negatively regulating PI3-K and p38 MAPK activity, respectively. Possible other CSF-1-dependent pro-survival pathways are indicated (?). The Akt- and p38 MAPK-dependent signaling pathways putatively involved in regulating macrophage apoptosis are also shown.