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

J Clin Invest. 2001 Jun;107(11):1375-85. doi: 10.1172/JCI10530.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Carrier Proteins / metabolism
  • Carrier Proteins / pharmacology*
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • DNA / metabolism
  • Glycoproteins / metabolism*
  • I-kappa B Proteins / metabolism
  • Immunohistochemistry
  • Interleukin-4 / metabolism
  • Interleukin-4 / pharmacology*
  • Macrophages / drug effects
  • Macrophages / physiology
  • Membrane Glycoproteins / metabolism
  • Membrane Glycoproteins / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / metabolism*
  • Osteoclasts / drug effects*
  • Osteoclasts / physiology
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Tumor Necrosis Factor
  • STAT6 Transcription Factor
  • Signal Transduction / physiology
  • Trans-Activators / metabolism*

Substances

  • Carrier Proteins
  • Glycoproteins
  • I-kappa B Proteins
  • Membrane Glycoproteins
  • NF-kappa B
  • Osteoprotegerin
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Tumor Necrosis Factor
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Tnfrsf11a protein, mouse
  • Tnfrsf11b protein, mouse
  • Tnfsf11 protein, mouse
  • Trans-Activators
  • Interleukin-4
  • DNA
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases