title: TNF-α is essential in the induction of fatal autoimmune hepatitis in mice through upregulation of hepatic CCL20 expression.
abstract: It is unclear what roles TNF-α has in the development of autoimmune hepatitis (AIH) and whether AIH is responsive to anti-TNF-α. We recently developed a mouse model of fatal AIH that develops in PD-1-deficient mice thymectomized three days after birth, finding that CCR6-CCL20 axis-dependent migration of dysregulated splenic T cells is crucial to induce AIH. In this study, we show the indispensable role of TNF-α in the development of AIH. Administering anti-TNF-α prevented the induction, but treatment by anti-TNF-α after the induction did not suppress progression. Administering anti-TNF-α did not prevent splenic T-cell activation, but did suppress hepatic CCL20 expression. In contrast, administering anti-CCL20 suppressed AIH but not elevated serum TNF-α levels. TNF-α stimulation enhanced CCL20 expression in hepatocytes. These findings suggest that TNF-α is essential in the induction of AIH through upregulation of hepatic CCL20 expression, which allows migration of dysregulated splenic T cells.
authors.affiliation: Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Iwamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kido
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Aoki
authors.forename: Hisayo
authors.initials: H
authors.lastname: Nishiura
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Maruoka
authors.forename: Aki
authors.initials: A
authors.lastname: Ikeda
authors.forename: Taku
authors.initials: T
authors.lastname: Okazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.forename: Norihiko
authors.initials: N
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013934:Thymectomy; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D014409:Tumor Necrosis Factor-alpha