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J. Biol. Chem., Vol. 279, Issue 52, 54039-54045, December 24, 2004

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Toll-like Receptor 9 Regulates Tumor Necrosis Factor- Expression by Different Mechanisms

IMPLICATIONS FOR OSTEOCLASTOGENESIS^*

Alla Amcheslavsky, Wei Zou, and Zvi Bar-Shavit

From the H. Hubert Humphrey Center for Experimental Medicine and Cancer Research, The Hebrew University Faculty of Medicine, P. O. Box 12272, Jerusalem 91120, Israel

CpG oligodeoxynucleotides (CpG-ODNs), mimicking bacterial DNA, stimulate osteoclastogenesis via Toll-like receptor 9 (TLR9) in receptor activator of NF-B ligand (RANKL)-primed osteoclast precursors. This activity is mediated via tumor necrosis factor (TNF)- induction by CpG-ODN. To further reveal the role of the cytokine in TLR9-mediated osteoclastogenesis, we compared the ability of CpG-ODN to induce osteoclastogenesis in two murine strains, BALB/c and C57BL/6, expressing different TNF- alleles. The induction of osteoclastogenesis and TNF- release by CpG-ODN was by far more noticeable in BALB/c-derived than in C57BL/6-derived osteoclast precursors. Unexpectedly, as revealed by Northern analysis, CpG-ODN induction of TNF- mRNA increase was more efficient in C57BL/6-derived cells. The cytokine transcript abundance was increased due to both increased message stability and rate of transcription. The difference between the two cell types was the result of a higher transcription rate in CpG-ODN-induced C57BL/6-derived cells caused by a single nucleotide polymorphism in B2a site within the TNF- promoter sequence. CpG-ODN enhanced the rate of the cytokine translation in BALB/c-derived cells. Thus, CpG-ODN modulated both transcription and translation of TNF-. The induction of transcription was more evident in C57BL/6-derived cells, while the induction of translation took place only in BALB/c-derived osteoclast precursors. Altogether the cytokine was induced to a larger extent in BALB/c-derived osteoclast precursors, consistent with the increased CpG-ODN osteoclastogenic effect in these cells.

Received for publication, August 10, 2004 , and in revised form, September 22, 2004.

^* This work was supported by Israel Science Foundation Grant 662-02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 972-2-67588363; Fax: 972-2-6414583; E-mail: barsha{at}cc.huji.ac.il.

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