T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6.
T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6.
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DOI：
10.1084/jem.179.5.1529
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发表时间：
1994-05-01
期刊：
影响因子：
--
通讯作者：
Fujiwara H
中科院分区：
文献类型：
--
作者：
Mizuhara H;O'Neill E;Seki N;Ogawa T;Kusunoki C;Otsuka K;Satoh S;Niwa M;Senoh H;Fujiwara H
本研究探讨了诱导和保护T细胞活化相关肝损伤的分子机制。当BALB/c小鼠单次静脉注射刀豆球蛋白A（Con A）（>或= 0.3 mg/小鼠）时，通过24 h内血浆转氨酶水平的显著升高来评估，它们发生急性肝损伤。组织学上，仅肝脏受损，汇管区和中央静脉周围有中度T细胞和多形性淋巴细胞浸润。肝损伤的诱导依赖于T细胞的存在以及活化，因为未经处理的BALB/c nu/nu小鼠或用T细胞特异性免疫抑制药物FK 506预处理的BALB/c小鼠未能发生疾病。在血浆转氨酶水平增加之前，检测到血浆中各种细胞因子水平的显著增加。在Con A注射后1小时内，肿瘤坏死因子（TNF）水平达到峰值，随后产生另外两种炎性细胞因子，白细胞介素6（IL-6）和IL-1。用抗-TNF而不是用抗-IL-1或抗-IL-6抗体被动免疫，赋予显著水平的保护。此外，在ConA注射前给予rIL-6导致IL-6剂量依赖性保护。单次给予给定剂量的rIL-6完全抑制转氨酶的释放，而相同的方案仅诱导40-50%的TNF产生抑制。超过80%的TNF产生抑制需要连续四次注射rIL-6。这些结果表明：（a）TNF是诱导T细胞活化相关（Con A诱导的）肝炎的关键细胞因子;（B）肝炎的诱导几乎完全由rIL-6控制;和（c）rIL-6通过多种机制（包括减少TNF产生）发挥其保护作用。
This study investigates the molecular mechanisms underlying the induction of and protection from T cell activation-associated hepatic injury. When BALB/c mice were given a single intravenous injection of concanavalin A (Con A) (> or = 0.3 mg/mouse), they developed acute hepatic injury as assessed by a striking increase in plasma transaminase levels within 24 h. Histopathologically, only the liver was injured while moderate infiltration of T cells and polymorphonuclear cells occurred in the portal areas and around the central veins. The induction of hepatic injury was dependent on the existence as well as the activation of T cells, as untreated BALB/c nu/nu mice or BALB/c mice pretreated with a T cell-specific immunosuppressive drug, FK506, failed to develop disease. Significant increases in the levels of various cytokines in the plasma were detected before an increase in plasma transaminase levels. Within 1 h after Con A injection, tumor necrosis factor (TNF) levels peaked, this being followed by production of two other inflammatory cytokines, interleukin 6 (IL-6) and IL-1. Passive immunization with anti-TNF but not with anti-IL-1 or anti-IL-6 antibody, conferred significant levels of protection. Moreover, administration of rIL-6 before Con A injection resulted in an IL-6 dose-dependent protection. A single administration of a given dose of rIL-6 completely inhibited the release of transaminases, whereas the same regimen induced only 40-50% inhibition of TNF production. More than 80% inhibition of TNF production required four consecutive rIL-6 injections. These results indicate that: (a) TNFs are critical cytokines for inducing T cell activation-associated (Con A-induced) hepatitis; (b) the induction of hepatitis is almost completely controlled by rIL-6; and (c) rIL-6 exerts its protective effect through multiple mechanisms including the reduction of TNF production.
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影响因子：
13.5
作者：
GILLES, PN;GUERRETTE, DL;CHISARI, FV
通讯作者：
CHISARI, FV
影响因子：
3.6
作者：
KEPPLER, D;LESCH, R;DECKER, K
通讯作者：
DECKER, K
影响因子：
15.9
作者：
KARMEN, A;WROBLEWSKI, F;LADUE, JS
通讯作者：
LADUE, JS
影响因子：
5.9
作者：
KERN, P;HEMMER, CJ;DIETRICH, M
通讯作者：
DIETRICH, M
影响因子：
15.3
作者：
LEHMANN, V;FREUDENBERG, MA;GALANOS, C
通讯作者：
GALANOS, C