Activation of T cells and pro-in ammatory cytokines are essential for human autoimmune hepatitis. The receptor for advanced glycation end-product(RAGE) is one of receptors for in ammatory alarm molecule high mobility group box 1 (HMGB1), and is involved in autoimmune hepatitis. However, the molecular mechanism of RAGE in setting of autoimmune hepatitis remains elusive. This study aimed to identify the function and mechanism of RAGE in autoimmune hepatitis. The RAGE de cient mouse was used to investigate the role and underlying mechanisms by which RAGE signaling-driven immune in ammatory response in the ConA-induced experimental hepatitis. We found that the RAGE de ciency protects the mouse from liver in ammatory injury caused by ConA challenge. mRNA expression of VCAM-1, IL-6, TNFα within the livers is markedly decreased in RAGE-de cient mice compared to wild-type mice. In parallel, RAGE de ciency leads to reduced levels of serum pro-in ammatory cytokines IL-6, TNF-α as compared to wild type control mice. RAGE-de cient mice exhibits increased of hepatic NK cells and decreased CD4 + T cells than those of wild type control mice. Notably, in vivo blockade of IL-6 in wild type mice signi cantly protected mice from ConA induced hepatic injury. Furthermore, RAGE de ciency impaired IL-6 production is associated with decreased expression of Arid5a in liver tissues, a half-life IL-6 mRNA regulator. RAGE signalling is important in regulating the development of autoimmune hepatitis. Immune modulation of RAGE may represent a novel therapeutic strategy to prevent immune-mediated liver injury.
Activation of T cells and pro-inflammatory cytokines are essential for human autoimmune hepatitis. The receptor for advanced glycation end-product(RAGE) is one of receptors for inflammatory alarm molecule high mobility group box 1 (HMGB1), and is involved in autoimmune hepatitis. However, the molecular mechanism of RAGE in setting of autoimmune hepatitis remains elusive. This study aimed to identify the function and mechanism of RAGE in autoimmune hepatitis. The RAGE deficient mouse was used to investigate the role and underlying mechanisms by which RAGE signaling-driven immune inflammatory response in the ConA-induced experimental hepatitis. We found that the RAGE deficiency protects the mouse from liver inflammatory injury caused by ConA challenge. mRNA expression of VCAM-1, IL-6, TNF-α within the livers is markedly decreased in RAGE-deficient mice compared to wild-type mice. In parallel, RAGE deficiency leads to reduced levels of serum pro-inflammatory cytokines IL-6, TNF-α as compared to wild type control mice. RAGE-deficient mice exhibits increased of hepatic NK cells and decreased CD4+ T cells than those of wild type control mice. Notably, in vivo blockade of IL-6 in wild type mice significantly protected mice from ConA induced hepatic injury. Furthermore, RAGE deficiency impaired IL-6 production is associated with decreased expression of Arid5a in liver tissues, a half-life IL-6 mRNA regulator. RAGE signalling is important in regulating the development of autoimmune hepatitis. Immune modulation of RAGE may represent a novel therapeutic strategy to prevent immune-mediated liver injury.
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