INTERFERON-INDUCIBLE PROTEIN-10 AND MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA INHIBIT GROWTH-FACTOR STIMULATION OF RAF-1 KINASE-ACTIVITY AND PROTEIN-SYNTHESIS IN A HUMAN GROWTH FACTOR-DEPENDENT HEMATOPOIETIC-CELL LINE (Retracted Article)
INTERFERON-INDUCIBLE PROTEIN-10 AND MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA INHIBIT GROWTH-FACTOR STIMULATION OF RAF-1 KINASE-ACTIVITY AND PROTEIN-SYNTHESIS IN A HUMAN GROWTH FACTOR-DEPENDENT HEMATOPOIETIC-CELL LINE (Retracted Article)
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DOI：
10.1074/jbc.270.37.21998
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发表时间：
1995-09-15
影响因子：
4.8
通讯作者：
BROXMEYER, HE
中科院分区：
文献类型：
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作者：
ARONICA, SM;MANTEL, C;BROXMEYER, HE
包括粒细胞-巨噬细胞集落刺激因子（GM-CSF）和钢因子（SLF）在内的刺激性细胞因子以协同方式起作用以刺激造血祖细胞的生长，这一作用也在生长因子依赖性人造血细胞系MO 7 e中得到证实。虽然对负责介导细胞因子的协同相互作用的机制知之甚少，但认为Raf-1（MAP激酶信号通路的组分）在由包括SLF和GM-CSF的几种细胞因子引起的刺激反应中起作用。干扰素诱导蛋白-10（IP-10）和巨噬细胞炎性蛋白-1 α（MIP-1 α）是抑制性细胞因子的趋化因子家族的成员。造血细胞预先暴露于趋化因子，包括IP-10和MIP-1 α，抑制生长因子对刺激细胞增殖的协同作用。我们报告，用GM-CSF和SLF的组合治疗MO 7 e细胞直接刺激Raf-1激酶的磷酸化和活化以及细胞蛋白质合成水平的统计学显著协同增加。用IP-10或MIP-1 α预处理MO 7 e细胞可阻断生长因子的协同作用，导致细胞增殖、蛋白质合成以及Raf-1磷酸化和活化的统计学显著抑制。IP-10和MIP-1 α处理也引起细胞内cAMP水平的显著增加。用用于提高细胞内cAMP水平的试剂或cAMP类似物预处理细胞以类似于IP-10和MIP-1 α的方式抑制GM-CSF和SLF的协同作用。此外，用cAMP依赖性蛋白激酶A的有效抑制剂处理细胞阻断了MIP-1 α和IP-10对Raf-1激酶活性和MO 7 e细胞增殖的抑制作用。IP-10和MIP-1 α拮抗GM-CSF和SLF协同作用的能力似乎涉及Raf-1的失活和蛋白质合成的下调。我们的研究结果表明，MIP-1 α和IP-10通过刺激细胞cAMP水平的增加和激活蛋白激酶A来介导它们在MO 7 e细胞中的抑制作用，我们认为这是这些趋化因子独有的机制，而不是适用于趋化因子超家族的所有生长抑制成员（例如，白细胞介素8和血小板因子4）。
Stimulatory cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF) and steel factor (SLF), act in a synergistic manner to stimulate the growth of hematopoietic progenitor cells, an effect also demonstrated for the growth factor-dependent human hematopoietic cell line MO7e. While little is known about the mechanisms responsible for mediating synergistic interactions of cytokines, Raf-1, a component of the MAP kinase signaling pathway, is thought to play a role in the stimulatory response evoked by several cytokines, including SLF and GM-CSF. Interferon-inducible protein-10 (IP-10) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) are members of the chemokine family of suppressive cytokines. Prior exposure of hematopoietic cells to chemokines, including IP-10 and MIP-1 alpha, inhibits the synergistic action of growth factors on stimulating cell proliferation. We report that treatment of MO7e cells with the combination of GM-CSF and SLF directly stimulates statistically significant synergistic increases in the phosphorylation and activation of Raf-1 kinase, and in cellular protein synthesis levels. Pretreatment of MO7e cells with IP-10 or MIP-1 alpha blocked synergistic growth factor action, resulting in statistically significant suppression of cell proliferation, protein synthesis, and Raf-1 phosphorylation and activation. IP-10 and MIP-1 alpha treatment also evoked significant increases in intracellular cAMP levels. Pretreatment of cells with agents which serve to raise intracellular cAMP levels, or with cAMP analogs inhibited the synergistic actions of GM-CSF and SLF in a manner similar to IP-10 and MIP-1 alpha. In addition, treatment of cells with a potent inhibitor of cAMP-dependent protein kinase A blocked the suppressive action of MIP-1 alpha and IP-10 on Raf-1 kinase activity and on MO7e cell proliferation. The ability of IP-10 and MIP-1 alpha to antagonize the synergistic action of GM-CSF and SLF appears to involve inactivation of Raf-1 and the down-regulation of protein synthesis. Our findings suggest that both MIP-1 alpha and IP-10 mediate their suppressive effects in MO7e cells by stimulating increases in cellular cAMP levels and activating protein kinase A, a mechanism we believe to be unique to these chemokines and not one applied to all growth suppressive members of the chemokine superfamily (for example, interleukin 8 and platelet factor 4).