Stimulation by TLR5 modulates osteoclast differentiation through STAT1/IFN-β
Stimulation by TLR5 modulates osteoclast differentiation through STAT1/IFN-β
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DOI：
10.4049/jimmunol.180.3.1382
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发表时间：
2008-02-01
影响因子：
4.4
通讯作者：
Lee, Zang Hee
中科院分区：
文献类型：
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作者：
Ha, Hyunil;Lee, Jong-Ho;Lee, Zang Hee
破骨细胞是从单核细胞-巨噬细胞谱系的造血前体细胞分化而来的骨吸收细胞。 TLR 的刺激已被证明可以积极或消极地调节破骨细胞分化，具体取决于实验条件。然而，这种调节发生的分子机制仍不清楚。在本研究中，我们检查了鞭毛蛋白（TLR5 的一种特定微生物配体）对 NF-κ B 配体受体激活剂 (RANKL) 刺激的破骨细胞生成的影响。鞭毛蛋白抑制 RANKL 对骨髓源性巨噬细胞中 c-Fos 蛋白表达的诱导，而不影响 c-Fos mRNA 表达。 c-Fos 的异位过度表达和 NFATc1 的组成型活性形式逆转了鞭毛蛋白诱导的抗破骨细胞生成作用。鞭毛蛋白的抑制作用是由 IFN-β 的产生介导的。鞭毛蛋白刺激骨髓源性巨噬细胞中 IFN-β 的表达和释放，而 IFN-β 中和抗体可阻止鞭毛蛋白诱导的 c-Fos 下调和抗破骨细胞生成作用。鞭毛蛋白、LPS 或 RANKL 诱导 IFN-β 基因依赖于 STAT1 激活。用鞭毛蛋白或 RANKL 治疗会刺激 STAT1 激活，而 STAT1 缺陷或 JAK2 抑制剂 AG490 会显着阻止响应鞭毛蛋白或 RANKL 的 IFN-β 诱导。此外，STAT1缺陷消除了鞭毛蛋白或LPS诱导的抗破骨细胞生成作用。相比之下，鞭毛蛋白在成骨细胞和骨髓细胞共培养物中刺激破骨细胞分化，而不诱导 IFN-β。因此，IFN-β 作为响应 TLR5 激活的破骨细胞生成的关键调节剂。
Osteoclasts are bone-resorbing cells that are differentiated from hemopoietic precursors of the monocyte-macrophage lineage. Stimulation of TLRs has been shown to positively or negatively modulate osteoclast differentiation, depending on the experimental condition. However, the molecular mechanism by which this modulation takes place remains unclear. In the present study, we examined the effects of flagellin, a specific microbial ligand of TLR5, on the receptor activator of NF-kappa B ligand (RANKL)stimulated osteoclastogenesis. Flagellin suppressed RANKL induction of c-Fos protein expression in bone marrow-derived macrophages without affecting c-Fos mRNA expression. Eetopic overexpression of c-Fos and a constitutively active form of NFATc1 reversed the flagellin-induced anti-osteoclastogenic effect. The inhibitory effect of fiagellin was mediated by IFN-beta production. Flagellin stimulated IFN-beta expression and release in bone marrow-derived macrophages, and IFN-beta-neutralizing Ab prevented the flagellin-induced c-Fos down-regulation and the anti-osteoclastogenic effect. IFN-beta gene induction by flagellin, LPS, or RANKL was dependent on STAT1 activation. Treatment with flagellin or RANKL stimulated STAT1 activation, and STAT1 deficiency or the JAK2 inhibitor AG490 dramatically prevented IFN-beta induction in response to flagellin or RANKL. In addition, STAT1 deficiency abolished the anti-osteoclastogenic effect induced by flagellin or LPS. In contrast, flagellin stimulated osteoclast differentiation in cocultures of osteoblasts and bone marrow cells without inducing IFN-beta. Thus, IFN-beta acts as a critical modulator of osteoclastogenesis in response to TLR5 activation.