Pivotal role of TARC, a CC chemokine, in bacteria-induced fulminant hepatic failure in mice
Pivotal role of TARC, a CC chemokine, in bacteria-induced fulminant hepatic failure in mice
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DOI：
10.1172/jci4619
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发表时间：
1998-12-01
影响因子：
15.9
通讯作者：
Matsushima, K
中科院分区：
文献类型：
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作者：
Yoneyama, H;Harada, A;Matsushima, K
胸腺和活化调节趋化因子（TARC）是最近发现的一种淋巴细胞导向的CC趋化因子，它特异性地吸引T辅助型2 CD4(+) T细胞。为了确定TARC在体内的病理生理作用，我们研究了针对TARC的单克隆抗体（mAb）是否能抑制痤疮丙酸杆菌和脂多糖（LPS）诱导的小鼠肝损伤模型。在启动阶段，痤疮杆菌诱导的肝内肉芽肿的形成对于随后由低剂量LPS引起的肝损伤是必不可少的。启动阶段似乎主要由Th1型免疫反应决定的趋化因子和趋化因子受体的表达谱。TARC是由肉芽肿形成细胞选择性产生的，并且在LPS处理后，表达CD4（+）的CC趋化因子受体4（CCR4）的T细胞迁移到肝脏。在LPS给药前体内注射抗tarc单抗可以保护小鼠免受急性致死性肝损伤，这伴随着肝脏浸润CD4(+) T细胞CCR4 mRNA表达和IL-4产生的显著降低。此外，抗tarc治疗降低了肝脏中tnf - α和Fas配体的表达。这些结果表明，肉芽肿源性TARC将产生il -4的CCR4(+) CD4(+) T细胞募集到肝实质可能是系统性LPS给药后大量肝损伤的关键原因。
Thymus and activation-regulated chemokine (TARC) is a recently identified lymphocyte-directed CC chemokine which specifically chemoattracts T helper type 2 CD4(+) T cells in human. To establish the pathophysiological roles of TARC in vivo, we investigated whether a monoclonal antibody (mAb) against TARC could inhibit the induction of hepatic lesions in murine model using Propionibacterium acnes and lipopolysaccharide (LPS). P. acnes-induced intrahepatic granuloma formation in the priming phase is essential to the subsequent liver injury elicited by a low dose of LPS. The priming phase appears to be dominated by Th1 type immune responses determined by the profile of chemokine and chemokine receptor expression. TARC was selectively produced by granuloma-forming cells, and CC chemokine receptor 4 (CCR4)-expressing CD4(+) T cells migrated into the liver after LPS administration. In vivo injection of anti-TARC mAb just before LPS administration protected the mice from acute lethal liver damage, which was accompanied by a significant reduction of both CCR4 mRNA expression and IL-4 production by liver-infiltrating CD4(+) T cells. Moreover, both TNF-alpha and Fas ligand expressions in the liver were decreased by anti-TARC treatment. These results suggest that recruitment of IL-4-producing CCR4(+) CD4(+) T cells by granuloma-derived TARC into the liver parenchyma may be a key cause of massive liver injury after systemic LPS administration.