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ANALYSES OF ROLE OF CD3^<int>IL-2Rbeta^+T CELLS IN ENDOTOXIN-INDUCED LIVER INJURY

CD3^<int>IL-2Rbeta^T细胞在内毒素性肝损伤中的作用分析

基本信息

批准号：
09670347
负责人：
MATSUI Kiyoshi
金额：
$ 1.73万
依托单位：
HYOGO COLLEGE OF MEDICINE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

Sequential administration of Propionibacterium acnes (P.acnes) and LPS induces liver injury in C57/BL6, BALB/c and BALB/c nu/nu (nude) mice. This hepatic injury model consists of two phases, priming and effector. During the priming phase, P.acnes-elicited Kupffer cells produce IL-12, that shifts hepatic T cells to type 1 cells that produce IFN-gamma. IL-12 also activates hepatic NK cells. During effector phase, P.acnes-primed and LPS-elicited Kupffer cells promptly produce TNF-alpha, IL-12 and IL-18. IL-12 and IL-18 activate hepatic lymphocytes to produce IFN-gamma, which in turn additionally activate Kupffer cells to produce more amount of TNF-alpha, a potent death factor. IL-18 also induces expression of functional Fas ligand, a second death factor, on hepatic lymphocytes. Since hepatocytes constitutively express Fas, induction of functional Fas lignad on hepatic lymphocytes directly leads to death of hepatocytes. Thus, we assume that during the priming phase with P.acnes. IL-12 is a … More key molecule that induces Th1 dominant condition and during the effector phase with LPS.IL-18 induces death factors to lead to liver injury.Thus, we investigated whether IL-12 replaces P.acnes and IL-18 replaces LPS.When lL-12 was administered instead of P.acnes, a challenge with either LPS, IL-12, IL-18 or IL-12 plus IL-18 did not induce liver injury. In contrast, either treatment induced liver injury in the mice that had been primed with P.acnes.Next, we identified the cell type that expresses FasL and characterized the role of FasL-expressing cells in induction of this liver injury in BALB/c nu/nu (nude) mice. In the hepatic lesion, apoptotic hepatocytes were closely apposed to NK cells. Hepatic lymphocytes from nude mice included NK cells and T cells. Only hepatic NK cells expressed FasL after LPS challenge. NK cell depletion rendered the mice resistant to this liver injury in association with impaired induction of FasL.We investigated whether cloned hepatic NK cells from P.acnes-primed nude mice increase FasL expression and show hepatotoxicity in response to IL-18. IL-18 enhanced surface FasL expression on cloned hepatic NK cells, which was responsible for apoptosis-inducing activity against hepatocytes in vitro. Furthermore, adoptive transfer of IL-18-stimulated cloned hepatic NK cells induced liver injury in the P.acnes-primed nude mice, whereas transfer of those additionally treated with anti-FasL mAb failed. These results suggest that the liver injury is caused by hepatic NK cells that express FasL in response to IL-18 after LPS challenge in nude mice. Less

痤疮丙酸杆菌和脂多糖序贯给药对C57/BL6、BALB/c和BALB/c nu/nu(裸)小鼠的肝损伤作用。该肝损伤模型包括启动和效应两个阶段。在启动阶段，痤疮杆菌诱导的库普弗细胞产生IL-12，将肝脏T细胞转变为产生干扰素-γ的1型细胞。IL-12还能激活肝脏NK细胞。在效应期，痤疮肺炎杆菌和脂多糖诱导的枯否细胞迅速产生肿瘤坏死因子-α、白介素12和白介素18。IL-12和IL-18激活肝脏淋巴细胞产生干扰素-γ，进而激活库普弗细胞产生更多的肿瘤坏死因子-α，这是一种强有力的死亡因子。IL-18还诱导肝淋巴细胞表达功能性Fas配体，这是第二个死亡因子。由于肝细胞固有地表达Fas，诱导肝淋巴细胞上功能性Fas木质素的表达直接导致肝细胞死亡。因此，我们假设在痤疮肺炎杆菌的启动阶段。IL-12是一种…IL-18可诱导死亡因子导致肝损伤，因此，我们研究了IL-12是否替代痤疮肺炎杆菌，而IL-18是否替代了痤疮肺炎杆菌。当用IL-12替代痤疮肺炎杆菌时，无论是用内毒素、IL-12、IL-18或IL-12与IL-18联合激发，均未引起肝损伤。接下来，我们鉴定了表达FasL的细胞类型，并表征了表达FasL的细胞在诱导BALB/c nu/nu(Nude)小鼠肝损伤中的作用。在肝损伤中，凋亡的肝细胞与NK细胞密切相关。裸鼠肝淋巴细胞包括NK细胞和T细胞。只有肝NK细胞在内毒素攻击后表达FasL。NK细胞的耗竭使小鼠对这种肝损伤产生抵抗，并与FasL的诱导受损有关。我们研究了从痤疮杆菌免疫的裸鼠中克隆的肝NK细胞是否增加了FasL的表达，并在IL-18的应答下表现出肝毒性。IL-18可促进克隆肝NK细胞表面FasL的表达，这可能是IL-18体外诱导肝细胞凋亡的机制之一。此外，过继转移IL-18刺激的克隆肝NK细胞可引起痤疮假单胞菌诱导的裸鼠肝损伤，而抗FasL单抗过继转移失败。这些结果提示，肝细胞损伤是由肝脏NK细胞在内毒素攻击后表达FasL，以应答IL-18所致。较少