Gruber M F, Williams C C, Gerrard T L
Division of Cytokine Biology, Food and Drug Administration, Bethesda, MD 20892.
J Immunol. 1994 Feb 1;152(3):1354-61.
Macrophage (M)-CSF is a survival and differentiation factor for mononuclear phagocytes. Stimulation of human monocytes with immobilized mAb directed to CD45 induces M-CSF message and small amounts of protein, which is strongly augmented by costimulation with IL-1 beta. This study was undertaken to study the mechanisms leading to the IL-1 beta-induced up-regulation of M-CSF production and to determine how the antiinflammatory cytokines, IL-4 and IL-10, affect M-CSF production in this system. We demonstrate that IL-1 beta enhanced M-CSF mRNA levels, in part, by increasing M-CSF gene transcription but had no effect on M-CSF message half-life. The enhancement of M-CSF message levels in the presence of IL-1 beta was blocked by cycloheximide, suggesting that de novo protein synthesis was required. Moreover, soluble IL-1 receptors inhibited the effect of IL-1 beta on M-CSF production thus confirming that these effects were IL-1 receptor mediated. Both IL-4 and IL-10 strongly inhibited M-CSF secretion by anti-CD45/IL-1 beta-induced monocytes that was accompanied by decreased M-CSF message levels. IL-4 and IL-10 repressed M-CSF gene transcription but did not affect M-CSF message half-life. These findings demonstrate that IL-1 beta, at least in part, transcriptionally up-regulates M-CSF production in anti-CD45-stimulated human monocytes, a process that can be negatively regulated by both IL-4 and IL-10. These results suggest that IL-1 beta, IL-4, and IL-10 control the survival and differentiation of human monocytes through a regulation of autocrine M-CSF production.
巨噬细胞（M）-集落刺激因子是单核吞噬细胞的生存和分化因子。用针对CD45的固定化单克隆抗体刺激人单核细胞可诱导M-集落刺激因子信息和少量蛋白质产生，白细胞介素-1β的共刺激可使其显著增加。本研究旨在探讨导致白细胞介素-1β诱导M-集落刺激因子产生上调的机制，并确定抗炎细胞因子白细胞介素-4和白细胞介素-10如何影响该系统中M-集落刺激因子的产生。我们证明，白细胞介素-1β部分通过增加M-集落刺激因子基因转录来提高其信使核糖核酸水平，但对M-集落刺激因子信息的半衰期没有影响。在白细胞介素-1β存在的情况下，M-集落刺激因子信息水平的提高被放线菌酮阻断，这表明需要重新合成蛋白质。此外，可溶性白细胞介素-1受体抑制白细胞介素-1β对M-集落刺激因子产生的影响，从而证实这些作用是由白细胞介素-1受体介导的。白细胞介素-4和白细胞介素-10均强烈抑制抗CD45/白细胞介素-1β诱导的单核细胞分泌M-集落刺激因子，同时M-集落刺激因子信息水平降低。白细胞介素-4和白细胞介素-10抑制M-集落刺激因子基因转录，但不影响M-集落刺激因子信息的半衰期。这些发现表明，白细胞介素-1β至少部分通过转录上调抗CD45刺激的人单核细胞中M-集落刺激因子的产生，这一过程可被白细胞介素-4和白细胞介素-10负调控。这些结果表明，白细胞介素-1β、白细胞介素-4和白细胞介素-10通过调节自分泌M-集落刺激因子的产生来控制人单核细胞的生存和分化。
