IL-1 mediates TNF-induced osteoclastogenesis.
IL-1 mediates TNF-induced osteoclastogenesis.
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DOI：
10.1172/jci23394
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发表时间：
2005-02
期刊：
影响因子：
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通讯作者：
S. Wei;H. Kitaura;P. Zhou;F. Ross;S. Teitelbaum
中科院分区：
文献类型：
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作者：
S. Wei;H. Kitaura;P. Zhou;F. Ross;S. Teitelbaum
骨髓基质细胞合成TNF诱导的受体激活因子NF-κ B配体（RANKL）是炎性骨质溶解的基本组成部分。我们发现，这一过程被废除的IL-1受体拮抗剂（IL-1 Ra）或在基质细胞来自I型IL-1受体缺陷（IL-1 RI缺陷）小鼠。反映了细胞因子TNF和IL-1的顺序信号传导，TNF诱导基质细胞表达IL-1和IL-1 RI。这些数据表明TNF通过IL-1调节RANKL表达，因此，IL-1在TNF诱导的关节周围骨质溶解中起作用。与这种姿势一致，在由暴露于IL-1 Ra的WT骨髓巨噬细胞和基质细胞组成的培养物中或在与IL-1 RI缺陷基质细胞建立的共培养物中，TNF刺激的破骨细胞生成减少约50%。体内TNF给药后，IL-1 RI缺陷小鼠中发生了相同程度的破骨细胞抑制。与TNF一样，IL-1直接靶向破骨细胞前体，并在允许水平的RANKL存在下以TNF非依赖性方式促进破骨细胞表型。IL-1能够诱导基质细胞表达RANKL，并在p38 MAPK的保护下直接刺激破骨细胞前体分化。因此，IL-1通过增强RANKL的基质细胞表达和直接刺激破骨细胞前体的分化来介导TNF的破骨细胞生成作用。
TNF-induced receptor activator NF-kappaB ligand (RANKL) synthesis by bone marrow stromal cells is a fundamental component of inflammatory osteolysis. We found that this process was abolished by IL-1 receptor antagonist (IL-1Ra) or in stromal cells derived from type I IL-1 receptor-deficient (IL-1RI-deficient) mice. Reflecting sequential signaling of the cytokines TNF and IL-1, TNF induces stromal cell expression of IL-1 and IL-1RI. These data suggest that TNF regulates RANKL expression via IL-1, and, therefore, IL-1 plays a role in TNF-induced periarticular osteolysis. Consistent with this posture, TNF-stimulated osteoclastogenesis in cultures consisting of WT marrow macrophages and stromal cells exposed to IL-1Ra or in cocultures established with IL-1RI-deficient stromal cells was reduced approximately 50%. The same magnitude of osteoclast inhibition occurred in IL-1RI-deficient mice following TNF administration in vivo. Like TNF, IL-1 directly targeted osteoclast precursors and promoted the osteoclast phenotype in a TNF-independent manner in the presence of permissive levels of RANKL. IL-1 is able to induce RANKL expression by stromal cells and directly stimulate osteoclast precursor differentiation under the aegis of p38 MAPK. Thus, IL-1 mediates the osteoclastogenic effect of TNF by enhancing stromal cell expression of RANKL and directly stimulating differentiation of osteoclast precursors.