Roles of the mitogen-activated protein kinase family in macrophage responses to colony stimulating factor-1 addition and withdrawal.
Colony stimulating factor-1 (CSF-1) (or macrophage CSF) is involved in the survival, proliferation, differentiation, and activation of cells of the monocyte/macrophage lineage. Because the mitogen-activated protein kinase family members extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinase are widely implicated in such cellular functions, we measured their activity in growing and growth-arrested cultures of bone marrow-derived macrophages (BMM), as well as their stimulation by saturating concentrations of CSF-1. ERK activity was approximately 2-fold higher in cycling BMM compared with growth-arrested BMM; in addition, CSF-1-stimulated BMM DNA synthesis was partially inhibited by PD98059, a specific inhibitor of MEK activation, suggesting a role for a mitogen-activated protein-ERK kinase (MEK)/ERK pathway in the control of DNA synthesis but surprisingly not in the control of cyclin D1 mRNA or c-myc mRNA expression. The suppression of BMM apoptosis by CSF-1, i.e. enhanced survival, was not reversed by PD98059, suggesting that a MEK/ERK pathway is not involved in this process. Using a quantitative kinase assay, it was found that CSF-1 gave a slight increase in BMM p38 activity, supporting prior data that CSF-1 is a relatively weak stimulator of inflammatory cytokine production in monocytes/macrophages. Relatively high concentrations of the p38 inhibitor, SKB202190, suppressed CSF-1-stimulated BMM DNA synthesis. No evidence could be obtained for the involvement of p38 activity in BMM apoptosis following CSF-1 withdrawal. We were not able to show that CSF-1 enhanced BMM JNK-1 activity to a significant extent; again, no role could be found for JNK-1 activity in the BMM apoptosis occurring after CSF-1 removal.
D000818:Animals; D001853:Bone Marrow; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured; D048728:MAP Kinase Kinase Kinase 1; D016173:Macrophage Colony-Stimulating Factor / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases