Yoneyama H, Harada A, Imai T, Baba M, Yoshie O, Zhang Y, Higashi H, Murai M, Asakura H, Matsushima K
Department of Molecular Preventive Medicine, School of Medicine, and CREST, The University of Tokyo, Tokyo 113, Japan.
J Clin Invest. 1998 Dec 1;102(11):1933-41. doi: 10.1172/JCI4619.
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.
胸腺与激活调节趋化因子（TARC）是一种最近发现的淋巴细胞趋化性CC趋化因子，它能特异性地趋化人辅助性T细胞2型CD4(+) T细胞。为了确定TARC在体内的病理生理作用，我们研究了抗TARC单克隆抗体（mAb）是否能在痤疮丙酸杆菌和脂多糖（LPS）诱导的小鼠模型中抑制肝脏损伤的发生。痤疮丙酸杆菌在启动阶段诱导肝内肉芽肿形成对于随后低剂量LPS引发的肝损伤至关重要。启动阶段似乎由趋化因子和趋化因子受体表达谱决定的Th1型免疫反应主导。TARC由肉芽肿形成细胞选择性产生，且LPS给药后，表达CC趋化因子受体4（CCR4）的CD4(+) T细胞迁移至肝脏。在LPS给药前体内注射抗TARC mAb可保护小鼠免受急性致死性肝损伤，同时肝内浸润的CD4(+) T细胞的CCR4 mRNA表达和IL-4产生均显著降低。此外，抗TARC治疗可降低肝脏中TNF-α和Fas配体的表达。这些结果表明，肉芽肿来源的TARC将产生IL-4的CCR4(+) CD4(+) T细胞募集到肝实质中可能是全身LPS给药后发生大规模肝损伤的关键原因。
