Evans R, Shultz L D, Dranoff G, Fuller J A, Kamdar S J
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
J Leukoc Biol. 1998 Dec;64(6):810-6. doi: 10.1002/jlb.64.6.810.
We test the hypothesis that the monocyte-macrophage colony-stimulating factor (CSF-1 or M-CSF) plays a major role in the inflammatory responses of Mphi by acting as a priming agent that heightens their responsiveness to secondary stimulation by other mediators. We previously reported that CSF-1 induced peritoneal Mphi (PMphi) to transcribe several genes including interleukin-6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm). It was reported that the Il6 and Csfgm genes were individually regulated by different pathways but it was not clear to what extent the two genes interacted during Mphi-mediated inflammatory responses. We now show that CSF-1 induces the release of bioactive GM-CSF from mouse resident PMphi. GM-CSF induces Il6 gene expression and synergizes with CSF-1 to induce the release of large amounts of IL-6. PMphi from C57BL/6J-Csfgm(null) mice were shown to release minimal IL-6 in response to CSF-1 and to express a much reduced response to the highly stimulatory combination of CSF-1 and lipopolysaccharide (LPS). Exogenous recombinant GM-CSF restored the IL-6 response of GM-CSF null PMphi to a great extent but not completely. As controls, three other recombinant proteins were tested but of these only tumor necrosis factor alpha (TNF-alpha) was shown to synergize with both CSF-1 and GM-CSF. Using PMphi from mice deficient in the expression of the Il6 gene, it was shown that they released two- to threefold more GM-CSF in response to CSF-1 than their control counterparts. However, an exogenous supply of recombinant IL-6 had no effect on GM-CSF release. The data indicate that the pathways regulating Il6 gene expression are under the control of a complex network of cytokine interactions involving at least CSF-1, GM-CSF, and TNF-alpha, with the added possibility that IL-6 may exert modulatory activity within this network.
单核细胞-巨噬细胞集落刺激因子（CSF-1 或 M-CSF）通过作为一种启动因子，增强巨噬细胞（Mphi）对其他介质二次刺激的反应性，在 Mphi 的炎症反应中起主要作用。我们之前报道过，CSF-1 诱导腹膜巨噬细胞（PMphi）转录多个基因，包括白细胞介素-6（Il6）和粒细胞-巨噬细胞集落刺激因子（Csfgm）。据报道，Il6 和 Csfgm 基因分别由不同途径调控，但在 Mphi 介导的炎症反应过程中，这两个基因的相互作用程度尚不清楚。我们现在表明，CSF-1 诱导小鼠驻留 PMphi 释放生物活性 GM-CSF。GM-CSF 诱导 Il6 基因表达，并与 CSF-1 协同诱导大量 IL-6 的释放。结果显示，来自 C57BL/6J-Csfgm（缺失）小鼠的 PMphi 对 CSF-1 的反应释放的 IL-6 极少，并且对 CSF-1 和脂多糖（LPS）的高刺激组合表现出明显降低的反应。外源性重组 GM-CSF 在很大程度上恢复了 GM-CSF 缺失的 PMphi 的 IL-6 反应，但并非完全恢复。作为对照，测试了其他三种重组蛋白，但其中只有肿瘤坏死因子α（TNF-α）显示与 CSF-1 和 GM-CSF 都有协同作用。使用 Il6 基因表达缺陷小鼠的 PMphi，结果表明，与对照相比，它们对 CSF-1 的反应释放的 GM-CSF 多两到三倍。然而，外源性供应重组 IL-6 对 GM-CSF 的释放没有影响。数据表明，调节 Il6 基因表达的途径受至少涉及 CSF-1、GM-CSF 和 TNF-α 的细胞因子相互作用复杂网络的控制，此外 IL-6 可能在该网络内发挥调节活性。
