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IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-κB
Yousef Abu-Amer
Yousef Abu-Amer
Published June 1, 2001
Citation Information: J Clin Invest. 2001;107(11):1375-1385. https://doi.org/10.1172/JCI10530.
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Article

IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-κB

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Abstract

IL-4, an anti-inflammatory cytokine, inhibits osteoclast differentiation, but the basis of this effect has been unclear. Osteoclastogenesis requires activation of RANK, which exerts its biologic effect via activation of NF-κB. NF-κB activation is manifested by nuclear translocation and binding to DNA, events secondary to phosphorylation and dissociation of IκBα. It is shown here that IL-4 reduces NF-κB nuclear translocation by inhibiting IκB phosphorylation, thus markedly inhibiting NF-κB DNA binding activity and blocking osteoclastogenesis entirely. Residual translocation of NF-κB in the presence of IL-4, however, suggests that nuclear mechanisms must primarily account for inhibition of NF-κB DNA binding and blockade of osteoclastogenesis. To address this issue, this study examined whether IL-4–induced STAT6 transcription factor blocks NF-κB transactivation. The results show that excess unlabeled consensus sequence STAT6, but not its mutated form, inhibits NF-κB binding. Furthermore, exogenously added STAT6 protein inhibits NF-κB/DNA interaction. Further supporting a role for STAT6 in this process are the findings that IL-4 fails to block osteoclastogenesis in STAT6–/– mice but that this blockade can be restored with addition of exogenous STAT6. Thus, IL-4 obliterates osteoclast differentiation by antagonizing NF-κB activation in a STAT6-dependent manner.

Authors

Yousef Abu-Amer

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Figure 2

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IL-4 inhibits NF-κB DNA binding activity. (a) Pure population of bone ma...
IL-4 inhibits NF-κB DNA binding activity. (a) Pure population of bone marrow macrophages was grown to confluence for 4 days in the presence of M-CSF. Cells were then treated with 10 ng/ml mIL-4 for 1 hour followed by 20 ng/ml RANKL as indicated. At the end of treatment, cells were harvested, nuclear extracts were prepared, and NF-κB EMSA was performed as described in Methods. Similar results represent three independent experiments. Incomplete inhibition of RANKL-induced NF-κB by IL-4 in lanes 5 and 6 correlates with basal expression of NF-κB under IL-4–treated conditions (lane 4), which does not support osteoclastogenesis. Extracts from 10- and 20-minute TNF-treated cells (10 ng/ml) were included as a positive control. (b) Identity of the NF-κB band was confirmed by binding with various NF-κB subunit antibodies (1 μl/reaction) as indicated or by a representative nonimmune IgG (lane 2). (c) Specificity of NF-κB binding was assessed by the addition of 50-fold (50×) unlabeled or mutated oligonucleotides, resulting in complete displacement or lack of displacement of the labeled probe, respectively.

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