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-kappaB. NF-kappaB activation is manifested by nuclear translocation and binding to DNA, events secondary to phosphorylation and dissociation of IkappaBalpha. It is shown here that IL-4 reduces NF-kappaB nuclear translocation by inhibiting IkappaB phosphorylation, thus markedly inhibiting NF-kappaB DNA binding activity and blocking osteoclastogenesis entirely. Residual translocation of NF-kappaB in the presence of IL-4, however, suggests that nuclear mechanisms must primarily account for inhibition of NF-kappaB DNA binding and blockade of osteoclastogenesis. To address this issue, this study examined whether IL-4-induced STAT6 transcription factor blocks NF-kappaB transactivation. The results show that excess unlabeled consensus sequence STAT6, but not its mutated form, inhibits NF-kappaB binding. Furthermore, exogenously added STAT6 protein inhibits NF-kappaB/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-kappaB activation in a STAT6-dependent manner.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bone Marrow Cells / metabolism
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Carrier Proteins / metabolism
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Carrier Proteins / pharmacology*
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Cell Differentiation / drug effects*
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Cell Differentiation / physiology
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Cell Nucleus / metabolism
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Cells, Cultured
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DNA / metabolism
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Glycoproteins / metabolism*
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I-kappa B Proteins / metabolism
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Immunohistochemistry
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Interleukin-4 / metabolism
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Interleukin-4 / pharmacology*
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Macrophages / drug effects
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Macrophages / physiology
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / pharmacology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Knockout
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / metabolism*
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Osteoclasts / drug effects*
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Osteoclasts / physiology
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Tumor Necrosis Factor
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STAT6 Transcription Factor
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Signal Transduction / physiology
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Trans-Activators / metabolism*
Substances
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Carrier Proteins
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Glycoproteins
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I-kappa B Proteins
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Membrane Glycoproteins
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NF-kappa B
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Osteoprotegerin
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Trans-Activators
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Interleukin-4
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DNA
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases