Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: Up-regulating eotaxins and IL-5 and recruiting leukocytes
Crucial role of IL-4/STAT6 in T cell-mediated hepatitis: Up-regulating eotaxins and IL-5 and recruiting leukocytes
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DOI：
10.4049/jimmunol.171.6.3233
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发表时间：
2003-09-15
影响因子：
4.4
通讯作者：
Gao, B
中科院分区：
文献类型：
--
作者：
Jaruga, B;Hong, F;Gao, B
T细胞介导的免疫应答与多种肝脏疾病的发病机制有关;然而，其潜在机制仍不清楚。Con A注射是研究T细胞介导的肝损伤的广泛接受的小鼠模型，其中STAT 6被快速激活。通过基因敲除的方式破坏IL-4和STAT 6基因消除了Con A介导的肝损伤，而不影响IFN-γ/STAT 1、IL-6/STAT 3或TNF-α/NF-κ B信号传导或影响NKT细胞活化。与野生型小鼠相比，IL-4（-/-）和STAT 6（-/-）小鼠中Con A诱导的肝炎中中性粒细胞和嗜酸性粒细胞的浸润明显受到抑制。IL-4处理诱导从野生型小鼠分离的肝细胞和窦状内皮细胞中的嗜酸性粒细胞趋化因子表达，但不诱导从STAT 6（-/-）小鼠分离的肝细胞和窦状内皮细胞中的嗜酸性粒细胞趋化因子表达。Con A注射诱导肝脏中嗜酸性粒细胞趋化因子的表达并升高IL-5和嗜酸性粒细胞趋化因子的血清水平;这种诱导在IL-4（-/-）和STAT 6（-/-）小鼠中显著减弱。最后，阻断嗜酸性粒细胞活化趋化因子可减轻刀豆蛋白A诱导的肝损伤和白细胞浸润。综上所述，这些发现表明IL-4/STAT 6通过增强肝细胞和窦内皮细胞中嗜酸性粒细胞趋化因子的表达在Con A诱导的肝炎中起关键作用，并诱导IL-5表达，从而促进嗜酸性粒细胞和中性粒细胞募集到肝脏中并导致肝炎。
T cell-mediated immune responses are implicated in the pathogenesis of a variety of liver disorders; however, the underlying mechanism remains obscure. Con A injection is a widely accepted mouse model to study T cell-mediated liver injury, in which STAT6 is rapidly activated. Disruption of the IL-4 and STAT6 gene by way of genetic knockout abolishes Con A-mediated liver injury without affecting IFN-gamma/STAT1, IL-6/STAT3, or TNF-alpha/NF-kappaB signaling or affecting NKT cell activation. Infiltration of neutrophils and eosinophils in Con A-induced hepatitis is markedly suppressed in IL-4(-/-) and STAT6(-/-) mice compared with wild-type mice. IL-4 treatment induces expression of eotaxins in hepatocytes and sinusoidal endothelial cells isolated from wildtype mice but not from STAT6(-/-) mice. Con A injection induces expression of eotaxins in the liver and elevates serum levels of IL-5 and eotaxins; such induction is markedly attenuated in IL-4(-/-) and STAT6(-/-) mice. Finally, eotaxin blockade attenuates Con A-induced liver injury and leukocyte infiltration. Taken together, these findings suggest that IL-4/STAT6 plays a critical role in Con A-induced hepatitis, via enhancing expression of eotaxins in hepatocytes and sinusoidal endothelial cells, and induces IL-5 expression, thereby facilitating recruitment of eosinophils and neutrophils into the liver and resulting in hepatitis.