title: Pathological activation of canonical nuclear-factor κB by synergy of tumor necrosis factor α and TNF-like weak inducer of apoptosis in mouse acute colitis.
abstract: Tumor necrosis factor (TNF)-α is a major effector in various inflammatory conditions. TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that promotes inflammatory tissue damage through its receptor, FGF-inducible molecule 14 (Fn14). Since both TWEAK and TNF-α have been shown to mediate pathological responses through inter-dependent or independent pathways by in vitro, the potential interplay of these pathways was investigated in a mouse colitis model. Acute colitis was induced by rectal injection of trinitrobenzene sulfonic acid (TNBS), with administration of control IgG, TNF receptor (TNFR)-Ig chimeric protein, anti-TWEAK monoclonal antibody, or the combination of TNFR-Ig and anti-TWEAK antibody. On day 4, disease severity was evaluated and gene expression profiling was analyzed using whole colon tissue. NF-κB activation was investigated with Western blot. Levels of transcript of TWEAK, Fn14 and NF-κB-related molecules were measured in purified colon epithelial cells (ECs). As a result, activation of the canonical (p50/RelA), but not noncanonical (p100/RelB)-mediated pathway was the hallmark of inflammatory responses in this model. Inflammation induced upregulation of Fn14 only in ECs but not in other cell types. Combination treatment of TNFR-Ig and anti-TWEAK antibody synergistically reduced disease severity in comparison with the control antibody or single agent treatment. Gene expression profile of the colon indicated downregulation of canonical NF-κB pathway with combination treatment. In conclusion, synergistic activation of canonical NF-κB by TWEAK and TNF-α is critical for the induction of inflammatory tissue damage in acute inflammation.
authors.affiliation: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan. Electronic address: dohi@ri.ncgm.go.jp.
authors.forename: Taeko
authors.initials: T
authors.lastname: Dohi
authors.affiliation: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan; Kitasato University Graduate School of Medical Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0373, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Kawashima
authors.affiliation: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.
authors.forename: Yuki I
authors.initials: YI
authors.lastname: Kawamura
authors.affiliation: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Otsubo
authors.affiliation: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan.
authors.forename: Teruki
authors.initials: T
authors.lastname: Hagiwara
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: Aldo
authors.initials: A
authors.lastname: Amatucci
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Michaelson
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D003106:Colon / Q000166:cytology / Q000473:pathology; D000074049:Cytokine TWEAK; D020869:Gene Expression Profiling; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000378:metabolism*; D000074050:TWEAK Receptor; D051996:Transcription Factor RelA / Q000096:biosynthesis; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D018124:Receptors, Tumor Necrosis Factor; C498144:Rela protein, mouse; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D014302:Trinitrobenzenesulfonic Acid
keywords: Acute colitis; Cytokines; Epithelial cell