The differential time-course of extracellular-regulated kinase activity correlates with the macrophage response toward proliferation or activation

Bone marrow-derived macrophages proliferate in response to specific growth factors, including macrophage colony-stimulating factor (M-CSF), When stimu lated with activating factors, such as lipopolysaccharide (LPS), macrophage s stop proliferating and produce proinflammatory cytokines, Although trigge ring opposed responses, both M-CSF and LPS induce the activation of extrace llular-regulated kinases (ERKs) 1 and 2. However, the time-course of ERK ac tivation is different; maximal activation by M-CSF and LPS occurred after 5 and 15 min of stimulation, respectively. Granulocyte/macrophage colony-sti mulating factor, interleukin 3, and TPA, all of which induced macrophage pr oliferation, also induced ERK activity, which was maximal at 5 min poststim ulation, The use of PD98059, which specifically blocks ERK 1 and 2 activati on, demonstrated that ERK activity was necessary for macrophage proliferati on in response to these factors. The treatment with phosphatidylcholine-spe cific phospholipase C (PC-PLC) inhibited macrophage proliferation, induced the expression of cytokines, and triggered a pattern of ERK activation equi valent to that induced by LPS, Moreover, PD98059 inhibited the expression o f cytokines induced by LPS or PC-PLC, thus suggesting that ERK activity is also required for macrophage activation by these two agents. Activation of the JNK pathway did not discriminate between proliferative and activating s timuli. In conclusion, our results allow to correlate the differences in th e time-course of ERK activity with the macrophase response toward prolifera tion or activation.