title: NF-κB signaling participates in both RANKL- and IL-4-induced macrophage fusion: receptor cross-talk leads to alterations in NF-κB pathways.
abstract: NF-κB activation is essential for receptor activator for NF-κB ligand (RANKL)-induced osteoclast formation. IL-4 is known to inhibit the RANKL-induced osteoclast differentiation while at the same time promoting macrophage fusion to form multinucleated giant cells (MNG). Several groups have proposed that IL-4 inhibition of osteoclastogenesis is mediated by suppressing the RANKL-induced activation of NF-κB. However, we found that IL-4 did not block proximal, canonical NF-κB signaling. Instead, we found that IL-4 inhibited alternative NF-κB signaling and induced p105/50 expression. Interestingly, in nfκb1(-/-) bone marrow-derived macrophages (BMM), the formation of both multinucleated osteoclast and MNG induced by RANKL or IL-4, respectively, was impaired. This suggests that NF-κB signaling also plays an important role in IL-4-induced macrophage fusion. Indeed, we found that the RANKL-induced and IL-4-induced macrophage fusion were both inhibited by the NF-κB inhibitors IκB kinase 2 inhibitor and NF-κB essential modulator inhibitory peptide. Furthermore, overexpression of p50, p65, p52, and RelB individually in nfκb1(-/-) or nfκb1(+/+) BMM enhanced both giant osteoclast and MNG formation. Interestingly, knockdown of nfκb2 in wild-type BMM dramatically enhanced both osteoclast and MNG formation. In addition, both RANKL- and IL-4-induced macrophage fusion were impaired in NF-κB-inducing kinase(-/-) BMM. These results suggest IL-4 influences NF-κB pathways by increasing p105/p50 and suppressing RANKL-induced p52 translocation and that NF-κB pathways participate in both RANKL- and IL-4-induced giant cell formation.
authors: Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors: Minjun
authors: M
authors: Yu
authors: Xiulan
authors: X
authors: Qi
authors: Jose L
authors: JL
authors: Moreno
authors: Donna L
authors: DL
authors: Farber
authors: Achsah D
authors: AD
authors: Keegan
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D002459:Cell Fusion; D002478:Cells, Cultured; D015726:Giant Cells / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D010010:Osteoclasts / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D053245:RANK Ligand / Q000235:genetics / Q000276:immunology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D015847:Interleukin-4; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D053245:RANK Ligand; D000097782:NF-kappaB-Inducing Kinase; C505689:Tnfsf11 protein, mouse