Interleukin-4 inhibits RANKL-induced NFATc1 expression via STAT6: a novel mechanism mediating its blockade of osteoclastogenesis.
Interleukin-4 inhibits RANKL-induced NFATc1 expression via STAT6: a novel mechanism mediating its blockade of osteoclastogenesis.
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DOI：
10.1002/jcb.23269
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发表时间：
2011-11
影响因子：
4
通讯作者：
Wei, Shi
中科院分区：
文献类型：
--
作者：
Cheng, Jing;Liu, Jianzhong;Shi, Zhenqi;Xu, Duorong;Luo, Shaokai;Siegal, Gene P.;Feng, Xu;Wei, Shi
白细胞介素-4（IL-4）是一种重要的免疫调节蛋白，具有有效的抗破骨细胞生成特性，并通过转录因子STAT 6实现。先前的研究表明，IL-4选择性地阻断RANKL诱导的NF-κB和丝裂原活化蛋白激酶（MAPK）通路分子的活化，表明细胞因子通过阻断这些信号级联来阻止破骨细胞生成。然而，对这些途径的抑制作用需要长时间的IL-4预处理，并且RANKL短期预暴露于破骨细胞前体后细胞因子未能发挥抗破骨细胞生成作用，这一事实表明，还可能涉及其他更直接的机制。在这项研究中，我们发现同时暴露于IL-4并没有改变NF-κB或MAPK的RANKL依赖性活化，而细胞因子确实阻断了RANKL诱导的核因子活化T细胞c1（NFATc 1），一种主要的破骨细胞生成转录因子。IL-4的这种抑制作用需要STAT 6，这与其在破骨细胞生成中的功能作用一致。此外，细胞因子也部分损害RANKL刺激的骨吸收。此外，IL-4以STAT 6依赖性方式抑制RANKL诱导的破骨细胞特异性基因的表达，但当破骨细胞前体预先暴露于RANKL时，IL-4未能做到这一点。因此，我们提供了第一个证据表明，IL-4通过抑制RANKL诱导NFATc 1通过STAT 6作为一个早期事件，除了其抑制其他信号传导途径，抑制破骨细胞的形成。抑制作用最终在基因表达转录水平上调节。
Interleukin-4 (IL-4) is an important immune regulatory protein that possesses potent anti-osteoclastogenic properties, and does so via the transcription factor STAT6. Previous studies have shown that IL-4 selectively blocks RANKL-induced activation of NF-κB and mitogen-activated protein kinase (MAPK) pathway molecules, suggesting that the cytokine arrests osteoclastogenesis by blockade of these signaling cascades. However, the fact that the inhibitory effect on these pathways requires prolonged IL-4 pretreatment, and that the cytokine fails to exert an anti-osteoclastogenic effect after short-term pre-exposure of RANKL to osteoclast precursors, suggests that an additional, more immediate mechanism may also be involved. In this study, we found that simultaneous exposure of IL-4 did not alter RANKL-dependent activation of NF-κB or MAPKs, whereas the cytokine did block RANKL-induced nuclear factor activated T cells c1 (NFATc1), a master osteoclastogenic transcription factor. This inhibitory effect of IL-4 required STAT6, consistent with its functional role in osteoclastogenesis. In addition, the cytokine also partially impaired RANKL-stimulated bone resorption. Furthermore, IL-4 suppressed expression of RANKL-induced osteoclast specific genes in a STAT6-dependent manner, but failed to do so when osteoclast precursors were pre-exposed to RANKL. Thus, we provide the first evidence that IL-4 inhibits osteoclast formation by inhibiting RANKL induction of NFATc1 via STAT6 as an early event, in addition to its suppression of other signaling pathways. The inhibitory effect is ultimately regulated at the gene expression transcriptional level.
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影响因子：
3.5
作者：
Song, Insun;Kim, Jung Ha;Kim, Nacksung
通讯作者：
Kim, Nacksung
影响因子：
15.3
作者：
Asagiri, M;Sato, K;Takayanagi, H
通讯作者：
Takayanagi, H
影响因子：
3.1
作者：
Rho, J;Altman, CR;Choi, Y
通讯作者：
Choi, Y
影响因子：
4.8
作者：
Wei, S;Wang, MWH;Ross, FP
通讯作者：
Ross, FP
影响因子：
4.4
作者：
Mangashetti, LS;Khapli, SM;Wani, MR
通讯作者：
Wani, MR