Plasmodium berghei Infection in Mice Induces Liver Injury by an IL-12- and Toll-Like Receptor/Myeloid Differentiation Factor 88-Dependent Mechanism1
Plasmodium berghei Infection in Mice Induces Liver Injury by an IL-12- and Toll-Like Receptor/Myeloid Differentiation Factor 88-Dependent Mechanism1
复制标题
小鼠伯氏疟原虫感染通过 IL-12 和 Toll 样受体/骨髓分化因子 88 依赖性机制诱导肝损伤1
作者：
K. Adachi;H. Tsutsui;S. Kashiwamura;E. Seki;Hiroki Nakano;O. Takeuchi;K. Takeda;K. Okumura;L. Van Kaer;H. Okamura;S. Akira;K. Nakanishi
疟疾是由疟原虫感染引起的，是一种生命周期特异性疾病，包括寄生虫红细胞阶段的肝损伤。在这项研究中，我们已经调查了伯氏疟原虫引起的肝损伤，其特征在于存在的凋亡和坏死的肝细胞和密集的淋巴细胞浸润的机制。尽管感染后IL-12和IL-18血清水平均升高，但IL-12缺陷型小鼠对伯氏疟原虫诱导的肝损伤具有抗性，而IL-18缺陷型小鼠则没有。在髓样分化因子88（MyD 88）缺陷的小鼠中，既没有观察到血清IL-12水平的升高，也没有观察到肝损伤，MyD 88是Toll样受体（TLR）共享的衔接分子。这些结果证明了在伯氏疟原虫感染期间TLR-MyD 88途径对于诱导IL-12产生的需要。伯氏疟原虫感染的野生型小鼠的肝淋巴细胞裂解未感染和感染小鼠的肝细胞。这些细胞的肝细胞毒性作用被穿孔素抑制剂阻断，但不被中和性抗Fas配体Ab阻断，并且被IL-12上调。令人惊讶的是，这些细胞以不受MHC限制的方式杀死肝细胞。然而，缺乏CD 1d限制性NK T细胞的CD 1d缺陷小鼠对伯氏疟原虫诱导的肝损伤易感。总的来说，我们的结果表明，由伯氏疟原虫感染小鼠诱导的肝损伤诱导TLR-MyD 88信号通路的激活，这导致IL-12的产生和MHC非限制性肝淋巴细胞的穿孔素依赖性细胞毒活性的激活。
Malaria, caused by infection with Plasmodium spp., is a life cycle-specific disease that includes liver injury at the erythrocyte stage of the parasite. In this study, we have investigated the mechanisms underlying Plasmodium berghei-induced liver injury, which is characterized by the presence of apoptotic and necrotic hepatocytes and dense infiltration of lymphocytes. Although both IL-12 and IL-18 serum levels were elevated after infection, IL-12-deficient, but not IL-18-deficient, mice were resistant to liver injury induced by P. berghei. Neither elevation of serum IL-12 levels nor liver injury was observed in mice deficient in myeloid differentiation factor 88 (MyD88), an adaptor molecule shared by Toll-like receptors (TLRs). These results demonstrated a requirement of the TLR-MyD88 pathway for induction of IL-12 production during P. berghei infection. Hepatic lymphocytes from P. berghei-infected wild-type mice lysed hepatocytes from both uninfected and infected mice. The hepatocytotoxic action of these cells was blocked by a perforin inhibitor but not by a neutralizing anti-Fas ligand Ab and was up-regulated by IL-12. Surprisingly, these cells killed hepatocytes in an MHC-unrestricted manner. However, CD1d-deficient mice that lack CD1d-restricted NK T cells, were susceptible to liver injury induced by P. berghei. Collectively, our results indicate that the liver injury induced by P. berghei infection of mice induces activation of the TLR-MyD88 signaling pathway which results in IL-12 production and activation of the perforin-dependent cytotoxic activities of MHC-unrestricted hepatic lymphocytes.
影响因子：
32.4
作者：
Mendiratta, SK;Martin, WD;VanKaer, L
通讯作者：
VanKaer, L
DOI：
10.1073/pnas.96.20.11543
发表时间：
1999-09
影响因子：
11.1
作者：
P. Wong;A. Kang;H. Chen;Q. Yuan;P. Fan;B. M. Sultzer;Y. Kan;S. Chung
通讯作者：
P. Wong;A. Kang;H. Chen;Q. Yuan;P. Fan;B. M. Sultzer;Y. Kan;S. Chung