Roles of the mitogen-activated protein kinase family in macrophage responses to colony stimulating factor-1 addition and withdrawal
Roles of the mitogen-activated protein kinase family in macrophage responses to colony stimulating factor-1 addition and withdrawal
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DOI：
10.1074/jbc.274.21.15127
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发表时间：
1999-05-21
影响因子：
4.8
通讯作者：
Hamilton, JA
中科院分区：
文献类型：
--
作者：
Jaworowski, A;Wilson, NJ;Hamilton, JA
集落刺激因子-1（CSF-1）（或巨噬细胞CSF）参与单核细胞/巨噬细胞谱系细胞的存活、增殖、分化和活化。由于促分裂原活化蛋白激酶家族成员细胞外信号调节激酶（ERK）、p38和c-Jun N-末端激酶广泛参与这些细胞功能，我们测量了它们在骨髓源性巨噬细胞（BMM）生长和生长停滞培养物中的活性，以及它们通过饱和浓度的CSF-1、与生长停滞的BMM相比，周期性BMM中ERK活性大约高出a倍;此外，CSF-1刺激的BMM DNA合成被MEK活化的特异性抑制剂PD 98059部分抑制，这表明促分裂原活化蛋白-ERK激酶（MEK）/ERK途径在控制DNA合成中的作用，但令人惊讶的是在控制细胞周期蛋白D1 mRNA或c-myc mRNA表达中没有作用。CSF-1对BMM细胞凋亡的抑制，即增强的存活率，没有被PD 98059逆转，表明MEK/ERK通路不参与该过程。使用定量激酶测定，发现CSF-1使BMM p38活性轻微增加，支持先前的数据，即CSF-1是单核细胞/巨噬细胞中炎性细胞因子产生的相对弱的刺激剂，相对高浓度的p38抑制剂SKB 202190抑制CSF-1刺激的BMM DNA合成。没有证据表明p38活性参与CSF-1停药后BMM细胞凋亡。我们不能证明CSF-1在显著程度上增强BMM JNK-1活性;同样，在CSF-1去除后发生的BMM细胞凋亡中没有发现JNK-1活性的作用。
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 a-fold higher in cycling BMM compared with growth-arrested BMM; in addition, CSF-l-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-l-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.