Ameliorated ConA-induced hepatitis in the absence of PKC-theta.
Ameliorated ConA-induced hepatitis in the absence of PKC-theta.
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DOI：
10.1371/journal.pone.0031174
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sun Z
中科院分区：
文献类型：
--
作者：
Fang X;Wang R;Ma J;Ding Y;Shang W;Sun Z
当免疫细胞错误地攻击个体自身的肝细胞时发生的严重肝损伤导致自身免疫性肝炎。在小鼠中，伴刀豆球蛋白A（ConA）治疗可以诱导急性肝炎，这会导致CD 1d阳性自然杀伤（NK）T细胞的快速激活。这些活化的NKT细胞产生大量的细胞因子，诱导强烈的炎症，损害肝组织。在这里，我们发现PKC-θ−/−小鼠对ConA诱导的肝炎具有抵抗力，这是由于PKC-θ在NKT细胞发育和活化中的重要功能。对野生型（WT）小鼠致死的ConA剂量（25 mg/kg）未能诱导PKC-θ−/−小鼠因肝损伤而死亡。相应地，在PKC-θ−/−小鼠中，ConA诱导的细胞因子（如IFNγ、IL-6和TNFα）的产生显著降低，这些细胞因子介导了导致肝损伤的炎症。在PKC-θ−/−小鼠中，外周NKT细胞在胸腺的早期阶段存在发育缺陷，因此其频率和数量大大减少。此外，将PKC-θ−/−骨髓过继转移至WT小鼠，在NKT细胞发育中显示出类似的缺陷，表明NKT细胞发育中对PKC-θ的内在需求。此外，在用NKT细胞特异性脂质配体刺激后，外周PKC-θ−/− NKT细胞产生的炎性细胞因子水平低于WT NKT细胞，表明NKT细胞的激活也需要PKC-θ。提示PKC-θ是激活NKT细胞诱导自身免疫性肝炎的重要分子，是预防自身免疫性肝炎的潜在药物靶点。
Severe liver injury that occurs when immune cells mistakenly attack an individual's own liver cells leads to autoimmune hepatitis. In mice, acute hepatitis can be induced by concanavalin A (ConA) treatment, which causes rapid activation of CD1d-positive natural killer (NK) T cells. These activated NKT cells produce large amounts of cytokines, which induce strong inflammation that damages liver tissues. Here we show that PKC-θ−/− mice were resistant to ConA-induced hepatitis due to essential function of PKC-θ in NKT cell development and activation. A dosage of ConA (25 mg/kg) that was lethal to wild-type (WT) mice failed to induce death resulting from liver injury in PKC-θ−/− mice. Correspondingly, ConA-induced production of cytokines such as IFNγ, IL-6, and TNFα, which mediate the inflammation responsible for liver injury, were significantly lower in PKC-θ−/− mice. Peripheral NKT cells had developmental defects at early stages in the thymus in PKC-θ−/− mice, and as a result their frequency and number were greatly reduced. Furthermore, PKC-θ−/− bone marrow adoptively transferred to WT mice displayed similar defects in NKT cell development, suggesting an intrinsic requirement for PKC-θ in NKT cell development. In addition, upon stimulation with NKT cell-specific lipid ligand, peripheral PKC-θ−/− NKT cells produced lower levels of inflammatory cytokines than that of WT NKT cells, suggesting that activation of NKT cells also requires PKC-θ. Our results suggest PKC-θ is an essential molecule required for activation of NKT cell to induce hepatitis, and thus, is a potential drug target for prevention of autoimmune hepatitis.
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影响因子：
15.3
作者：
Kaneko, Y;Harada, M;Kawano, T;Yamashita, M;Shibata, Y;Gejyo, F;Nakayama, T;Taniguchi, M
通讯作者：
Taniguchi, M
影响因子：
5.3
作者：
Lin, X;O'Mahony, A;Greene, WC
通讯作者：
Greene, WC
影响因子：
4.4
作者：
Manicassainy, Santhakumar;Sun, Zuoming
通讯作者：
Sun, Zuoming
DOI：
10.1073/pnas.040561297
发表时间：
2000-02-29
影响因子：
11.1
作者：
Faggioni, R;Jones-Carson, J;Fantuzzi, G
通讯作者：
Fantuzzi, G
DOI：
10.1084/jem.182.6.2091
发表时间：
1995-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bendelac A
通讯作者：
Bendelac A