Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation.
Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation.
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DOI：
10.1084/jem.185.6.1005
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发表时间：
1997-03-17
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我们已经建立了mRNA的差异显示聚合酶链反应，白细胞介素（IL）-18的成骨基质细胞表达。用于比较的基质细胞群在促进破骨细胞样多核细胞（OCL）形成的能力方面存在差异。发现IL-18的mRNA在不能支持OCL形成的细胞系中比在支持性细胞中以更高丰度表达。重组IL-18被发现在成骨细胞和脾或骨髓来源的造血细胞的共培养物中抑制OCL形成。在存在破骨细胞生成剂（包括1α，25-二羟维生素D3、前列腺素E2、甲状旁腺激素、IL-1和IL-11）的情况下，IL-18可抑制OCL形成。IL-18的抑制作用仅限于共培养的早期阶段，这与造血前体细胞的增殖相一致。据报道，IL-18可诱导T细胞产生干扰素-γ（IFN-γ）和粒细胞/巨噬细胞集落刺激因子（GM-CSF），这两种药物也可抑制体外OCL形成。抗GM-CSF的中和抗体能够挽救IL-18对OCL形成的抑制，而抗IFN-γ的中和抗体则不能。在与成骨细胞和IFN-γ受体II型缺陷小鼠的脾细胞共培养中，发现IL-18抑制OCL的形成，表明IL-18的作用独立于IFN-γ的产生：IFN-γ在这些共培养物中没有作用。此外，在共培养中，脾细胞来自受体缺陷型小鼠，成骨细胞来自野生型小鼠，反之亦然，我们确定IFN-γ抑制OCL形成的靶细胞是造血细胞。这项工作提供了证据表明，IL-18由成骨细胞表达，并通过GM-CSF的产生而不是通过IFN-γ的产生来抑制OCL的形成。
We have established by differential display polymerase chain reaction of mRNA that interleukin (IL)-18 is expressed by osteoblastic stromal cells. The stromal cell populations used for comparison differed in their ability to promote osteoclast-like multinucleated cell (OCL) formation. mRNA for IL-18 was found to be expressed in greater abundance in lines that were unable to support OCL formation than in supportive cells. Recombinant IL-18 was found to inhibit OCL formation in cocultures of osteoblasts and hemopoietic cells of spleen or bone marrow origin. IL-18 inhibited OCL formation in the presence of osteoclastogenic agents including 1α,25-dihydroxyvitamin D3, prostaglandin E2, parathyroid hormone, IL-1, and IL-11. The inhibitory effect of IL-18 was limited to the early phase of the cocultures, which coincides with proliferation of hemopoietic precursors. IL-18 has been reported to induce interferon-γ (IFN-γ) and granulocyte/macrophage colony-stimulating factor (GM–CSF) production in T cells, and both agents also inhibit OCL formation in vitro. Neutralizing antibodies to GM–CSF were able to rescue IL-18 inhibition of OCL formation, whereas neutralizing antibodies to IFN-γ did not. In cocultures with osteoblasts and spleen cells from IFN-γ receptor type II–deficient mice, IL-18 was found to inhibit OCL formation, indicating that IL-18 acted independently of IFN-γ production: IFN-γ had no effect in these cocultures. Additionally, in cocultures in which spleen cells were derived from receptor-deficient mice and osteoblasts were from wild-type mice and vice versa, we identified that the target cells for IFN-γ inhibition of OCL formation were the hemopoietic cells. The work provides evidence that IL-18 is expressed by osteoblasts and inhibits OCL formation via GM–CSF production and not via IFN-γ production.