title: Hepatic serum amyloid A1 aggravates T cell-mediated hepatitis by inducing chemokines via Toll-like receptor 2 in mice.
abstract: Serum amyloid A is a proinflammatory molecule that induces leukocyte infiltration and promotes neutrophil adhesion to endothelial cells under inflammatory conditions. The aim of this study was to examine whether Saa1 aggravates T cell-mediated hepatitis by inducing chemokines in a liver-specific, Saa1-overexpressing, transgenic (TG) mouse model. We generated TG mice in which Saa1 was overexpressed specifically in liver tissue. The chemokines monocyte chemotactic protein 1 (MCP1), MIP1α, MIP1β, interferon γ-induced protein 10 (IP-10), and eotaxin were induced in Saa1 TG mice. After concanavalin A treatment, Saa1 expression was higher in Saa1 TG mice than in WT mice. More severe liver injury, increased hepatocyte apoptosis, and higher levels of hepatic enzymes were observed in Saa1 TG mice than in WT mice. Liver infiltration of CD4(+) T cells and macrophages increased after inducing hepatitis. Activation of T cells was higher in Saa1 TG mice than in WT mice, and the populations of Th17 cells and regulatory T cells were altered by overexpressing Saa1 in TG mice. Secretion of various cytokines, such as interferon γ, tumor necrosis factor α, and interleukin 6, increased in Saa1 TG mice. Injecting a Toll-like receptor 2 (TLR2) antagonist in vivo inhibited chemokine expression and IκBα phosphorylation and showed that the induction of chemokines by Saa1 was dependent on TLR2. Hepatic Saa1 accelerated T cell-mediated hepatitis by inducing chemokine production and activating T cells by TLR2. Therefore, Saa1 might be a novel inflammatory factor that acts as a chemokine modulator in hepatitis.
authors.affiliation: From the School of Life Science, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Buk-gu, Daegu 702-701, Korea and.
authors.forename: Young Rae
authors.initials: YR
authors.lastname: Ji
authors.affiliation: From the School of Life Science, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Buk-gu, Daegu 702-701, Korea and.
authors.forename: Hei Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: From the School of Life Science, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Buk-gu, Daegu 702-701, Korea and.
authors.forename: Ki Beom
authors.initials: KB
authors.lastname: Bae
authors.affiliation: From the School of Life Science, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Buk-gu, Daegu 702-701, Korea and.
authors.forename: Sanggyu
authors.initials: S
authors.lastname: Lee
authors.affiliation: the Department of Animal Science, Kyungpook National University, Sangju 742-711, Korea.
authors.forename: Myoung Ok
authors.initials: MO
authors.lastname: Kim
authors.affiliation: From the School of Life Science, KNU Creative BioResearch Group (BK21 Plus Project), Kyungpook National University, Buk-gu, Daegu 702-701, Korea and jaewoong64@hanmail.net.
authors.forename: Zae Young
authors.initials: ZY
authors.lastname: Ryoo
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D003208:Concanavalin A / Q000009:adverse effects / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008934:Mitogens / Q000009:adverse effects / Q000494:pharmacology; D000685:Serum Amyloid A Protein / Q000096:biosynthesis* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; D008934:Mitogens; C489995:Saa2 protein, mouse; D000685:Serum Amyloid A Protein; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D003208:Concanavalin A
keywords: Saa1; T cell activation; Toll like receptor; chemokine; concanavalin A; cytokine; inflammation; liver injury; transgenic mice
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