Malchow Sven, Thaiss Wolfgang, Jänner Nathalie, Waetzig Georg H, Gewiese-Rabsch Jessica, Garbers Christoph, Yamamoto Kosuke, Rose-John Stefan, Scheller Jürgen
Institute of Biochemistry, Christian-Albrechts-University of Kiel, Kiel, Germany.
Biochim Biophys Acta. 2011 Mar;1812(3):290-301. doi: 10.1016/j.bbadis.2010.11.009. Epub 2010 Dec 2.
Neutrophil depleted mice are protected from concanavalin A-mediated hepatitis, showing that neutrophils are critical for cellular liver damage. Interleukin-6 has pro- and anti-inflammatory properties and mediates neutrophil recruitment in diseases such as rheumatoid arthritis. In classic signaling, interleukin-6 binds to the membrane-bound interleukin-6-receptor and initiates signaling via gp130. In interleukin-6 trans-signaling, the agonistic soluble interleukin-6-receptor can form a soluble interleukin-6/interleukin-6-receptor complex and stimulate cells which only express gp130 but no interleukin-6-receptor. Interleukin-6 trans-signaling was shown to be important for liver regeneration and development of liver adenomas. Here, we show that blocking classic interleukin-6 signaling but not interleukin-6 trans-signaling reduced concanavalin A-induced liver damage in mice, with reduced liver STAT3 phosphorylation and liver neutrophil accumulation. However, the level of neutrophil-attracting chemokine KC is only reduced by inhibition of interleukin-6 trans-signaling. Analysis of circulating neutrophils after concanavalin A challenge revealed that classic interleukin-6 signaling is required for the mobilization of blood neutrophils. Reduced neutrophil infiltration was accompanied by increased levels of hepatoprotective monocyte chemoattractant protein-1 and reduced level of hepatodestructive interleukin-4. Abrogated classic interleukin-6 signaling in concanavalin A-mediated hepatitis exhibited liver-protective effects indicating that interleukin-6 classic but not interleukin-6 trans-signaling is responsible for liver damage. Classic interleukin-6 signaling is required to mount an efficient neutrophilia during concanavalin A-induced immune response, which might have clinical implications in the regard that blocking global interleukin-6 signaling pathways is a treatment option in different chronic inflammatory diseases.
中性粒细胞减少的小鼠可免受伴刀豆球蛋白A介导的肝炎影响，这表明中性粒细胞对肝细胞损伤至关重要。白细胞介素-6具有促炎和抗炎特性，并在类风湿性关节炎等疾病中介导中性粒细胞募集。在经典信号传导中，白细胞介素-6与膜结合的白细胞介素-6受体结合，并通过gp130启动信号传导。在白细胞介素-6转信号传导中，激动性可溶性白细胞介素-6受体可形成可溶性白细胞介素-6/白细胞介素-6受体复合物，并刺激仅表达gp130但不表达白细胞介素-6受体的细胞。白细胞介素-6转信号传导对肝脏再生和肝腺瘤的发展很重要。在此，我们表明，阻断经典白细胞介素-6信号传导而非白细胞介素-6转信号传导可减少伴刀豆球蛋白A诱导的小鼠肝损伤，同时降低肝脏STAT3磷酸化和肝脏中性粒细胞积聚。然而，只有通过抑制白细胞介素-6转信号传导才能降低中性粒细胞趋化因子KC的水平。伴刀豆球蛋白A攻击后循环中性粒细胞的分析表明，经典白细胞介素-6信号传导是血液中性粒细胞动员所必需的。中性粒细胞浸润减少伴随着肝脏保护因子单核细胞趋化蛋白-1水平的增加和肝脏破坏因子白细胞介素-4水平的降低。在伴刀豆球蛋白A介导的肝炎中消除经典白细胞介素-6信号传导表现出肝脏保护作用，表明白细胞介素-6经典信号传导而非白细胞介素-6转信号传导导致肝脏损伤。在伴刀豆球蛋白A诱导的免疫反应期间，需要经典白细胞介素-6信号传导来引发有效的中性粒细胞增多，这在不同慢性炎症疾病中阻断全局白细胞介素-6信号通路是一种治疗选择方面可能具有临床意义。
