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

痤疮丙酸杆菌（P.acnes）和LPS的顺序施用诱导C57/BL 6、BALB/c和BALB/c nu/nu（裸）小鼠的肝损伤。该肝损伤模型包括两个阶段，启动和效应。在致敏阶段，痤疮丙酸杆菌诱导的枯否细胞产生IL-12，其将肝T细胞转变为产生IFN-γ的1型细胞。IL-12还激活肝NK细胞。在效应期，痤疮丙酸杆菌致敏和LPS诱导的库普弗细胞迅速产生TNF-α、IL-12和IL-18。IL-12和IL-18激活肝淋巴细胞产生IFN-γ，IFN-γ反过来又激活枯否细胞产生更多量的TNF-α，一种有效的死亡因子。IL-18还诱导肝淋巴细胞上功能性Fas配体（第二死亡因子）的表达。由于肝细胞组成性表达Fas，肝淋巴细胞上功能性Fas配体的诱导直接导致肝细胞死亡。因此，我们假设，在启动阶段与痤疮丙酸杆菌。IL-12是 ...更多信息 因此，我们研究了IL-12是否替代痤疮丙酸杆菌和IL-18是否替代LPS。当施用IL-12代替痤疮丙酸杆菌时，用LPS、IL-12、IL-18或IL-12加IL-18的攻击均不诱导肝损伤。与此相反，任何一种治疗诱导的小鼠，已经与痤疮丙酸杆菌引发的肝损伤。接下来，我们确定了细胞类型，表达FasL和特征的FasL表达细胞在诱导这种肝损伤的BALB/c nu/nu（裸）小鼠的作用。在肝损害中，凋亡的肝细胞与NK细胞紧密并列。裸鼠肝脏淋巴细胞包括NK细胞和T细胞。LPS刺激后，只有肝NK细胞表达FasL。NK细胞耗竭使小鼠对这种肝损伤具有抵抗力，这与FasL诱导受损有关。我们研究了从痤疮丙酸杆菌致敏的裸鼠克隆的肝NK细胞是否增加FasL表达，并显示对IL-18的肝毒性反应。IL-18增强克隆的肝NK细胞表面FasL的表达，这是负责体外对肝细胞的增殖诱导活性。此外，过继转移IL-18刺激的克隆肝NK细胞诱导痤疮丙酸杆菌致敏的裸鼠中的肝损伤，而转移额外用抗FasL mAb处理的那些失败。这些结果表明，肝损伤是由肝NK细胞表达FasL响应于IL-18在LPS攻击后在裸鼠中引起的。少

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