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

• Published in: The Journal of clinical investigation 2001-06, Vol.107 (11), p.1375-1385
• Main Author: Abu-Amer, Yousef
• Format: Article
• Language: English
• ISSN: 0021-9738
• DOI: 10.1172/JCI10530

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- Kappa B. NF- Kappa B activation is manifested by nuclear translocation and binding to DNA, events secondary to phosphorylation and dissociation of I Kappa B alpha . It is shown here that IL-4 reduces NF- Kappa B nuclear translocation by inhibiting I Kappa B phosphorylation, thus markedly inhibiting NF- Kappa B DNA binding activity and blocking osteoclastogenesis entirely. Residual translocation of NF- Kappa B in the presence of IL-4, however, suggests that nuclear mechanisms must primarily account for inhibition of NF- Kappa B DNA binding and blockade of osteoclastogenesis. To address this issue, this study examined whether IL-4-induced STAT6 transcription factor blocks NF- Kappa B transactivation. The results show that excess unlabeled consensus sequence STAT6, but not its mutated form, inhibits NF- Kappa B binding. Furthermore, exogenously added STAT6 protein inhibits NF- Kappa B/DNA interaction. Further supporting a role for STAT6 in this process are the findings that IL-4 fails to block osteoclastogenesis in STAT6 super(-/-) mice but that this blockade can be restored with addition of exogenous STAT6. Thus, IL-4 obliterates osteoclast differentiation by antagonizing NF- Kappa B activation in a STAT6-dependent manner.