Schultz R M
Lilly Research Laboratories, Indianapolis, IN 46285.
Immunopharmacol Immunotoxicol. 1991;13(1-2):183-98. doi: 10.3109/08923979109019699.
Recombinant human granulocyte/macrophage colony-stimulating factor (GM-CSF) induced significant superoxide production in human neutrophils within 30 minutes after addition of stimulus and the response was complete within 2 hr. Other agents known to prime neutrophils, including LPS and tumor necrosis factor-alpha, lacked activity under the experimental conditions employed. Using a panel of pharmacologic inhibitors, we sought to compare GM-CSF-induced neutrophil superoxide to that produced by cells exposed to N-formyl methionyl-leucyl-phenylalanine (fMet-Leu-Phe) and phorbol 12-myristate 13-acetate (PMA). Each stimulant displayed a different profile. Rolipram, a peak IV phosphodiesterase inhibitor, specifically inhibited neutrophil activation by GM-CSF and fMet-Leu-Phe, while superoxide production stimulated by PMA was unaffected. Staurosporine, a protein kinase C (PK-C) inhibitor, suppressed superoxide production induced by all three neutrophil stimulants. Cytochalasin B totally inhibited superoxide induced by GM-CSF under conditions that promote the fMet-Leu-Phe-induced response. Cytochalasin B did not markedly affect PMA-induced superoxide. The results are consistent with the hypothesis that intact PK-C activity is essential for neutrophil superoxide production, but that differences exist in the initial pathways induced by these neutrophil activators. Superoxide secretion from GM-CSF-treated neutrophils appears to be a direct, delayed response that requires assembly of microfilaments during exposure to the cytokine.
重组人粒细胞/巨噬细胞集落刺激因子（GM-CSF）在加入刺激物后30分钟内可诱导人中性粒细胞产生大量超氧化物，且该反应在2小时内完成。在所用实验条件下，其他已知能使中性粒细胞致敏的物质，包括脂多糖（LPS）和肿瘤坏死因子-α，均无活性。我们使用一组药理抑制剂，试图比较GM-CSF诱导的中性粒细胞超氧化物与暴露于N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMet-Leu-Phe）和佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）的细胞产生的超氧化物。每种刺激物呈现出不同的特征。罗利普兰，一种IV型磷酸二酯酶抑制剂，特异性抑制GM-CSF和fMet-Leu-Phe诱导的中性粒细胞活化，而PMA刺激产生的超氧化物不受影响。星形孢菌素，一种蛋白激酶C（PK-C）抑制剂，抑制所有三种中性粒细胞刺激物诱导的超氧化物产生。细胞松弛素B在促进fMet-Leu-Phe诱导反应的条件下完全抑制GM-CSF诱导的超氧化物。细胞松弛素B对PMA诱导的超氧化物没有明显影响。这些结果与以下假设一致，即完整的PK-C活性对于中性粒细胞超氧化物的产生至关重要，但这些中性粒细胞激活剂诱导的初始途径存在差异。GM-CSF处理的中性粒细胞分泌超氧化物似乎是一种直接的延迟反应，在暴露于细胞因子期间需要微丝组装。
