ERK5/BMK1 Is Indispensable for Optimal Colony-Stimulating Factor 1 (CSF-1)-Induced Proliferation in Macrophages in a Src-Dependent Fashion

• Published in: The Journal of immunology (1950) 2008-03, Vol.180 (6), p.4166-4172
• Main Authors: Rovida, Elisabetta, Spinelli, Elena, Sdelci, Sara, Barbetti, Valentina, Morandi, Andrea, Giuntoli, Serena, Dello Sbarba, Persio
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Transformed; Cell Line, Tumor; Cell Proliferation; Enzyme Activation - immunology; Humans; Macrophage Colony-Stimulating Factor - physiology; Macrophages - cytology; Macrophages - enzymology; Macrophages - metabolism; Mice; Mitogen-Activated Protein Kinase 7 - physiology; NIH 3T3 Cells; Receptor, Macrophage Colony-Stimulating Factor - physiology; src-Family Kinases - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.180.6.4166

CSF-1, by binding to its high-affinity receptor CSF-1R, sustains the survival and proliferation of monocyte/macrophages, which are central cells of innate immunity and inflammation. The MAPK ERK5 (also known as big MAPK-1, BMK1, or MAPK7) is a 98-kDa molecule sharing high homology with ERK1/2. ERK5 is activated by oxidative stress or growth factor stimulation. This study was undertaken to characterize ERK5 involvement in macrophage signaling that is elicited by CSF-1. Exposure to the CSF-1 of primary human macrophages or murine macrophage cell lines, as well as murine fibroblasts expressing ectopic CSF-1R, resulted in a rapid and sustained increase of ERK5 phosphorylation on activation-specific residues. In the BAC1.2F5 macrophage cell line, ERK5 was also activated by another mitogen, GM-CSF, while macrophage activators such as LPS or IFN-gamma and a number of nonproliferative cytokines failed. Src family kinases were found to link the activation of CSF-1R to that of ERK5, whereas protein kinase C or the serine phosphatases PP1 and PP2A seem not to be involved in the process. Treatment of macrophages with ERK5-specific small interfering RNA markedly reduced CSF-1-induced DNA synthesis and total c-Jun phosphorylation and expression, while increasing the expression of the cyclin-dependent kinase inhibitor p27. Following CSF-1 treatment, the active form of ERK5 rapidly translocated from cytosol to nucleus. Taken together, the results reported in this study show that ERK5 is indispensable for optimal CSF-1-induced proliferation and indicate a novel target for its control.