IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB.
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.
Abu-Amer
Y
Y
Department of Orthopedic Research and Department of Pathology, Barnes-Jewish Hospital at Washington University School of Medicine, St. Louis, Missouri, USA. abuamery@msnotes.wustl.edu
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*
D002352:Carrier Proteins; D006023:Glycoproteins; D020672:I-kappa B Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D004247:DNA; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases