C-C chemokine ligand 2/monocyte chemoattractant protein-1 directly inhibits NKT cell IL-4 production and is hepatoprotective in T cell-mediated hepatitis in the mouse
C-C chemokine ligand 2/monocyte chemoattractant protein-1 directly inhibits NKT cell IL-4 production and is hepatoprotective in T cell-mediated hepatitis in the mouse
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DOI：
10.4049/jimmunol.170.10.5252
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发表时间：
2003-05-15
影响因子：
4.4
通讯作者：
Swain, MG
中科院分区：
文献类型：
--
作者：
Ajuebor, MN;Hogaboam, CM;Swain, MG
T细胞介导的肝脏疾病与血清中C - C趋化因子配体2（CCL2）/单核细胞趋化蛋白 - 1（MCP - 1）水平升高有关。然而，CCL2/MCP - 1的作用在多大程度上促成了T细胞介导的肝炎的发病机制仍未完全清楚。刀豆蛋白A（Con A）诱导的肝炎是一种由活化的T细胞介导的肝脏特异性炎症，由肿瘤坏死因子 - α（TNF - α）、干扰素 - γ（IFN - γ）和白细胞介素 - 4（IL - 4）在肝脏中的表达上调所驱动。本研究检测了CCL2/MCP - 1在小鼠中由刀豆蛋白A给药诱导的T细胞介导的肝炎发病机制中的作用。我们证明了在刀豆蛋白A诱导的肝炎过程中CCL2/MCP - 1具有一种新的肝脏保护作用，因为在给予刀豆蛋白A后，CCL2/MCP - 1的中和作用在生化和组织学上都显著加重了肝脏损伤。此外，CCL2/MCP - 1的中和作用与肝脏中TNF - α和IFN - γ水平的显著降低有关，但与肝脏中IL - 4水平的显著升高有关。而且，在体外，重组MCP - 1（rMCP - 1）处理显著降低了刀豆蛋白A刺激的CD3⁺NK1.1⁺ T细胞产生IL - 4以及CCR2的表达。总之，我们提出CCL2/MCP - 1在T细胞介导的肝炎中通过直接刺激其特异性受体CCR2抑制CD3⁺NK1.1⁺ T细胞产生IL - 4，从而发挥一种新的抗炎作用。这些发现可能与T细胞介导的肝炎有直接的临床相关性。
T cell-mediated liver diseases are associated with elevated serum levels of C-C chemokine ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1). However, the extent to which the actions of CCL2/MCP-1 contribute to the pathogenesis of T cell-mediated hepatitis remains incompletely understood. Con A-induced hepatitis is a liver-specific inflammation mediated by activated T cells and is driven by an up-regulation of the hepatic expression of TNF-alpha, IFN-gamma, and IL-4. The present study examined the role of CCL2/MCP-1 in the pathogenesis of T cell-mediated hepatitis induced by Con A administration in the mouse. We demonstrate a novel hepatoprotective role for CCL2/MCP-1 during Con, A-induced hepatitis, because CCL2/MCP-1 neutralization strikingly enhanced hepatic injury, both biochemically and histologically, after Con A administration. Furthermore, CCL2/MCP-1 neutralization was associated with a significant reduction in the hepatic levels of TNF-alpha and IFN-gamma, but with a significant increase in hepatic IL-4 levels. Moreover, IL-4 production and CCR2 expression by Con A-stimulated CD3(+)NK1.1(+) T cells was significantly reduced by rMCP-1 treatment in vitro. In summary, we propose that CCL2/MCP-1 fulfills a novel anti-inflammatory role in T cell-mediated hepatitis by inhibiting CD3(+)NK1.1(+) T cell-derived IL-4 production through direct stimulation of its specific receptor CCR2. These findings may have direct clinical relevance to T cell-mediated hepatitis.