title: IFN-γ is reciprocally involved in the concurrent development of organ-specific autoimmunity in the liver and stomach.
abstract: Interferon (IFN)-γ acts as a critical proinflammatory mediator in autoimmune processes, whereas it exerts regulatory functions to limit tissue damage associated with inflammation. However, a detailed understanding of the complex roles of IFN-γ in the development of organ-specific autoimmunity is still lacking. Recently, we found that programmed cell death 1-deficient mice thymectomized 3 days after birth (NTx-PD-1(-/-) mice) concurrently developed autoimmune hepatitis (AIH) and autoimmune gastritis (AIG). In this study, we investigated the roles of IFN-γ in the development of AIH and AIG in this mouse model. In NTx-PD-1(-/-) mice, serum levels of IFN-γ were markedly elevated. Neutralization of IFN-γ prevented the development of AIG. However, the same treatment exacerbated hepatic T-cell infiltration in AIH. Because of the loss of anti-proliferative effects by IFN-γ, neutralization of IFN-γ increased T-cell proliferation in the spleen and liver, resulting in exacerbated T-cell infiltration in the liver. On the other hand, in the development of AIG, CD4+ T-cell migration into the gastric mucosa is essential for induction. CCL20 expression was up-regulated in the gastric mucosa, and anti-CCL20 suppressed CD4+ T-cell infiltration into the gastric mucosa. Importantly, anti-IFN-γ suppressed CCL20 expression and infiltration of CD4+ T cells in the gastric mucosa, whereas in vivo injection of recombinant IFN-γ up-regulated CCL20 expression in the stomach, suggesting that IFN-γ is critically involved in CD4+ T-cell accumulation in AIG by up-regulating local CCL20 expression. In conclusion, IFN-γ is involved differently in the development of AIH and of AIG. IFN-γ negatively regulates T-cell proliferation in fatal AIH, whereas it initiates development of AIG. These findings imply that increased production of IFN-γ induced by an organ-specific autoimmunity may trigger the concurrent development of another organ-specific autoimmune disease.
authors: Graduate School of Medicine, Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University, Kyoto 606-8501, Japan.
authors: Satoru
authors: S
authors: Iwamoto
authors: Masahiro
authors: M
authors: Kido
authors: Nobuhiro
authors: N
authors: Aoki
authors: Hisayo
authors: H
authors: Nishiura
authors: Ryutaro
authors: R
authors: Maruoka
authors: Aki
authors: A
authors: Ikeda
authors: Taku
authors: T
authors: Okazaki
authors: Tsutomu
authors: T
authors: Chiba
authors: Norihiko
authors: N
authors: Watanabe
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control; D015551:Autoimmunity / Q000276:immunology*; D054418:Chemokine CCL20 / Q000378:metabolism; D005753:Gastric Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005756:Gastritis / Q000276:immunology / Q000517:prevention & control; D019693:Hepatitis, Autoimmune / Q000276:immunology; D007371:Interferon-gamma / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D013270:Stomach / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D054418:Chemokine CCL20; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma