Interleukin (IL)-12 mediates the anti-osteoclastogenic activity of CpG-oligodeoxynucleotides
Interleukin (IL)-12 mediates the anti-osteoclastogenic activity of CpG-oligodeoxynucleotides
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DOI：
10.1002/jcp.20563
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发表时间：
2006-04-01
影响因子：
5.6
通讯作者：
Bar-Shavit, Z
中科院分区：
文献类型：
--
作者：
Amcheslavsky, A;Bar-Shavit, Z
细菌DNA通过与toll样受体9 （TLR9）的相互作用激活先天免疫系统。该受体识别CpG-寡脱氧核苷酸（CpG- odns），在某些序列背景下模仿CpG二核苷酸的特征DNA。大多数研究表明TLR配体增加破骨细胞分化。我们发现，早期破骨细胞前体中TLRs（特别是TLR4和TLR9）的激活导致nf - κ B配体受体激活剂（RANKL）诱导的破骨细胞分化受到抑制。我们的目标是确定导致TLR配体这种抑制作用的机制。由于RANKL- rank和CpG-ODN- tlr9相互作用导致NF-kappa B活化，p38和ERK磷酸化，以及tnf - α合成（都与破骨细胞生成有关），我们假设CpG-ODN（而不是RANKL）还诱导抗破骨细胞生成因子的合成。使用DNA阵列（GEArray Q Series Mouse NF-kappa B Signaling Pathway Gene Array, MM-016, SuperArray）研究对照破骨细胞前体和RANKLE CpG-ODN处理的细胞，或它们的组合。我们发现，在CpG-ODN和CpG-ODN + RANKL处理的破骨细胞前体中，破骨细胞生成抑制剂白细胞介素-12 （IL-12）的mRNA水平显著升高。北部和西部的分析，连同ELISA，证实了DNA阵列的研究。与这些发现相关，IL-12抑制rankl诱导的破骨细胞分化，特异性抗IL-12抗体抑制CpG-ODN的抗破骨作用。综上所述，TLR9被其配体CpG-ODN激活，导致IL-12的合成和释放，从而对抗rankl诱导的破骨细胞分化。
Bacterial DNA activates the innate immune system via interactions with Toll-like receptor 9 (TLR9). This receptor recognizes CpG-oligodeoxynucleotides (CpG-ODNs) mimicking the CpG dinucleotides in certain sequence contexts characterizing this DNA. Most Studies have shown increased osteoclast differentiation by TLR ligands. We found that activation of TLRs (specifically TLR4 and TLR9) in early osteoclast precursors results in inhibition of receptor activator of NF-kappa B ligand (RANKL)-induced osteoclast differentiation. Our objective is to identify the mechanism leading to this inhibitory effect of a TLR ligand. Since both RANKL-RANK and CpG-ODN-TLR9 interactions result in NF-kappa B activation, p38 and ERK phosphorylation, and TNF-alpha synthesis (all implicated in osteoclastogenesis), we hypothesized that CpG-ODN (but not RANKL) in addition induces the synthesis of an anti-osteoclastogenic factor. Control osteoclast precursors, and cells treated with RANKLE CpG-ODN, or their combination were Studied using DNA arrays (GEArray Q Series Mouse NF-kappa B Signaling Pathway Gene Array, MM-016, SuperArray). We found a marked increase in the mRNA levels of the osteoclastogenesis inhibitor interleukin-12 (IL-12) in osteoclast precursors treated with CpG-ODN and CpG-ODN + RANKL. Northern and Western analyses, together with ELISA, confirmed the DNA array studies. In correlation with these findings, IL-12 inhibited RANKL-induced osteoclast differentiation and specific anti-IL-12-antibodies inhibited the anti-osteoclastogenic effect of CpG-ODN. In conclusion, activation of TLR9 by its ligand, CpG-ODN, results in synthesis and release of IL-12 opposing RANKL-induced osteoclast differentiation.