Rovida Elisabetta, Spinelli Elena, Sdelci Sara, Barbetti Valentina, Morandi Andrea, Giuntoli Serena, Dello Sbarba Persio
Dipartimento di Patologia e Oncologia Sperimentali, Università degli Studi di Firenze, Florence, Italy.
J Immunol. 2008 Mar 15;180(6):4166-72. 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.
集落刺激因子-1（CSF-1）通过与其高亲和力受体CSF-1R结合，维持单核细胞/巨噬细胞的存活和增殖，而单核细胞/巨噬细胞是固有免疫和炎症的核心细胞。丝裂原活化蛋白激酶ERK5（也称为大丝裂原活化蛋白激酶-1、BMK1或MAPK7）是一种98 kDa的分子，与ERK1/2具有高度同源性。ERK5可被氧化应激或生长因子刺激激活。本研究旨在表征ERK5参与CSF-1引发的巨噬细胞信号传导的情况。将原代人巨噬细胞或小鼠巨噬细胞系以及表达异位CSF-1R的小鼠成纤维细胞暴露于CSF-1中，导致ERK5在激活特异性残基上的磷酸化迅速且持续增加。在BAC1.2F5巨噬细胞系中，ERK5也可被另一种促有丝分裂原GM-CSF激活，而巨噬细胞激活剂如脂多糖或干扰素-γ以及一些非增殖性细胞因子则不能激活。发现Src家族激酶将CSF-1R的激活与ERK5的激活联系起来，而蛋白激酶C或丝氨酸磷酸酶PP1和PP2A似乎不参与该过程。用ERK5特异性小干扰RNA处理巨噬细胞可显著降低CSF-1诱导的DNA合成以及总的c-Jun磷酸化和表达，同时增加细胞周期蛋白依赖性激酶抑制剂p27的表达。CSF-1处理后，ERK5的活性形式迅速从细胞质转移到细胞核。综上所述，本研究报告的结果表明ERK5对于CSF-1诱导的最佳增殖是不可或缺的，并指出了一个新的调控靶点。
