Wilson Nicholas J, Cross Maddalena, Nguyen Thao, Hamilton John A
Arthritis and Inflammation Research Centre, Department of Medicine (RMH/WH), University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.
FEBS J. 2005 Aug;272(16):4141-52. doi: 10.1111/j.1742-4658.2005.04826.x.
Macrophage colony stimulating factor (M-CSF) or CSF-1 controls the development of the macrophage lineage through its receptor tyrosine kinase, c-Fms. cAMP has been shown to influence proliferation and differentiation in many cell types, including macrophages. In addition, modulation of cellular ERK activity often occurs when cAMP levels are raised. We have shown previously that agents that increase cellular cAMP inhibited CSF-1-dependent proliferation in murine bone marrow-derived macrophages (BMM) which was associated with an enhanced extracellular signal-regulated kinase (ERK) activity. We report here that increasing cAMP levels, by addition of either 8-bromo cAMP (8BrcAMP) or prostaglandin E(1) (PGE1), can induce macrophage differentiation in M1 myeloid cells engineered to express the CSF-1 receptor (M1/WT cells) and can potentiate CSF-1-induced differentiation in the same cells. The enhanced CSF-1-dependent differentiation induced by raising cAMP levels correlated with enhanced ERK activity. Thus, elevated cAMP can promote either CSF-1-induced differentiation or inhibit CSF-1-induced proliferation depending on the cellular context. The mitogen-activated protein kinase/extracellular signal-related protein kinase kinase (MEK) inhibitor, PD98059, inhibited both the cAMP- and the CSF-1R-dependent macrophage differentiation of M1/WT cells suggesting that ERK activity might be important for differentiation in the M1/WT cells. Surprisingly, addition of 8BrcAMP or PGE1 to either CSF-1-treated M1/WT or BMM cells suppressed the CSF-1R-dependent tyrosine phosphorylation of cellular substrates, including that of the CSF-1R itself. It appears that there are at least two CSF-1-dependent pathway(s), one MEK/ERK dependent pathway and another controlling the bulk of the tyrosine phosphorylation, and that cAMP can modulate signalling through both of these pathways.
巨噬细胞集落刺激因子（M-CSF）或CSF-1通过其受体酪氨酸激酶c-Fms控制巨噬细胞谱系的发育。环磷酸腺苷（cAMP）已被证明可影响包括巨噬细胞在内的多种细胞类型的增殖和分化。此外，当cAMP水平升高时，细胞外信号调节激酶（ERK）活性通常会发生调节。我们之前已经表明，增加细胞内cAMP的试剂会抑制小鼠骨髓来源的巨噬细胞（BMM）中CSF-1依赖的增殖，这与增强的ERK活性相关。我们在此报告，通过添加8-溴环磷酸腺苷（8BrcAMP）或前列腺素E1（PGE1）来提高cAMP水平，可以在经过基因工程改造以表达CSF-1受体的M1髓样细胞（M1/WT细胞）中诱导巨噬细胞分化，并且可以增强同一细胞中CSF-1诱导的分化。提高cAMP水平所诱导的增强的CSF-1依赖的分化与增强的ERK活性相关。因此，根据细胞环境，升高的cAMP可以促进CSF-1诱导的分化或抑制CSF-1诱导的增殖。丝裂原活化蛋白激酶/细胞外信号相关蛋白激酶激酶（MEK）抑制剂PD98059抑制了M1/WT细胞中cAMP和CSF-1R依赖的巨噬细胞分化，这表明ERK活性可能对M1/WT细胞的分化很重要。令人惊讶的是，向CSF-1处理的M1/WT或BMM细胞中添加8BrcAMP或PGE1会抑制细胞底物包括CSF-1R自身的CSF-1R依赖的酪氨酸磷酸化。似乎至少存在两条CSF-1依赖的途径，一条是MEK/ERK依赖的途径，另一条控制大部分酪氨酸磷酸化，并且cAMP可以通过这两条途径调节信号传导。
