NF-(kappa)B-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis.
NF-(kappa)B is an important component of both autoimmunity and bone destruction in RA. NF-(kappa)B-inducing kinase (NIK) is a key mediator of the alternative arm of the NF-(kappa)B pathway, which is characterized by the nuclear translocation of RelB/p52 complexes. Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NF-kappaB ligand-stimulated osteoclastogenesis. We investigated the role of NIK in murine models of inflammatory arthritis using Nik-/- mice. The serum transfer arthritis model is initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While Nik-/- mice had inflammation equivalent to that of Nik+/+ controls, they showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, Nik-/- mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2-/- mice conferred susceptibility to AIA, while transfer of Nik-/- cells did not. Nik-/- mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2. Thus, NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.
Aya
Kunihiko
K
Department of Pathology and Immunology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Alhawagri
Muhammad
M
Hagen-Stapleton
Amanda
A
Kitaura
Hideki
H
Kanagawa
Osami
O
Novack
Deborah Veis
DV
D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology; D010010:Osteoclasts / Q000276:immunology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2