Hepatic serum amyloid A-1 aggravates T cell mediated hepatitis by inducing chemokines via Toll-like receptor 2 in mice [Molecular Bases of Disease]

April 6th, 2015 by Ji, Y. R., Kim, H. J., Bae, K. B., Lee, S., Kim, M. O., Ryoo, Z. Y.

Serum amyloid A (SAA) is a pro-inflammatory 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 gamma-induced protein 10 (IP-10), and eotaxin were induced in Saa1 TG mice. After ConA treatment, Saa1 expression was higher in Saa1 TG mice than in wild-type (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. Thus, Saa1 might be a novel inflammatory factor that acts as a chemokine modulator in hepatitis.
  • Posted in Journal of Biological Chemistry, Publications
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