Anti-inflammatory effect of cholera toxin B subunit in experimental stroke.
Anti-inflammatory effect of cholera toxin B subunit in experimental stroke.
复制标题
霍乱毒素 B 亚基对实验性脑卒中的抗炎作用。
DOI：
10.1186/s12974-016-0610-y
复制
发表时间：
2016-06-13
影响因子：
9.3
通讯作者：
Lu Z
中科院分区：
文献类型：
--
作者：
Zhang L;Huang Y;Lin Y;Shan Y;Tan S;Cai W;Li H;Zhang B;Men X;Lu Z
霍乱毒素B亚基（CTB）具有多方面的免疫调节功能。免疫在脑卒中发病机制中起重要作用。然而，对于CTB是否对中风有益，人们知之甚少。短暂局灶性缺血大鼠缺血后腹腔注射CTB。测量梗死体积、体重减轻和神经功能缺损。检测缺血脑细胞因子、小胶质细胞/巨噬细胞活化和转录因子。检测缺血脑半球分离的小胶质细胞/巨噬细胞中IL-1β和TNF-α mRNA的表达。对缺血脑内的γδT细胞、产生il -17的γδT细胞、Th17细胞和调节性T （Treg）细胞进行检测。同时观察外周血γδT细胞和Treg细胞的变化。CTB减少了缺血后的梗死面积、神经功能缺损和体重下降。缺血后24 h， CTB可下调IL-1β、TNF-α、NF-kB p65、磷酸化-ERK1/2和小胶质细胞/巨噬细胞活化水平，抑制NF-kB结合活性，但不影响ERK1/2水平。CTB治疗后，缺血半球分离的小胶质细胞/巨噬细胞中IL-1β和TNF-α的mRNA表达受到抑制。在缺血半球，CTB治疗在缺血后24和72 h降低了γδT细胞、产生IL-17的γδT细胞和IL-17的水平，而Th17细胞未受影响。经CTB治疗后，缺血后24 h Treg细胞、TGF-β、IL-10水平保持不变，72 h上调。抗cd25灭活Treg细胞可减弱CTB诱导的TGF-β和IL-10在缺血后72 h的升高。在缺血后24 h， CTB增加了外周血Treg细胞，抑制了γδT细胞。缺血72 h后，可使Treg细胞增加，但对γδT细胞无影响。CTB对小鼠脑内细胞因子、转录因子、浸润性γδT细胞和Treg细胞均无影响。在小鼠外周血中，CTB在24和72 h均使Treg细胞增加，而对γδT细胞无影响。CTB通过其免疫调节功能，包括抑制小胶质细胞/巨噬细胞活化，抑制γδT细胞，诱导Treg细胞产生，从而调节相关细胞因子的分泌，减轻脑缺血后的神经功能损害和组织损伤。抑制NF-kB和ERK1/2通路参与了CTB的神经保护机制。
Cholera toxin B subunit (CTB) has multifaceted immunoregulatory functions. Immunity plays an important role in the mechanism of stroke. However, little is known about whether CTB is beneficial for stroke. CTB was administered intraperitoneally after ischemia to rats subjected to transient focal ischemia. Infarct volumes, body weight loss, and neurologic deficits were measured. Cytokines, microglia/macrophage activation, and transcriptional factors in the ischemic brain were tested. The mRNA expressions of IL-1β and TNF-α were tested in the microglia/macrophage isolated from the ischemic hemisphere. γδT cells, IL-17-producing γδT cells, Th17 cells, and regulatory T (Treg) cells in the ischemic brain were tested. γδT cells and Treg cells in the peripheral blood were also evaluated. CTB reduced infarct volumes, neurologic deficits, and body weight loss after ischemia. At 24 h after ischemia, CTB downregulated the levels of IL-1β, TNF-α, NF-kB p65, phosphorylated-ERK1/2, and microglia/macrophage activation and suppressed NF-kB binding activity, but did not affect the level of ERK1/2. The mRNA expressions of IL-1β and TNF-α in the microglia/macrophage isolated from the ischemic hemisphere were suppressed after CTB therapy. In the ischemic hemisphere, CTB treatment reduced the levels of γδT cells, IL-17-producing γδT cells, and IL-17 at both 24 and 72 h after ischemia, while Th17 cells were not affected. After CTB treatment, the levels of Treg cells, TGF-β, and IL-10 remained unchanged at 24 h and upregulated at 72 h after ischemia. Inactivation of Treg cells using anti-CD25 attenuated the increase of TGF-β and IL-10 induced by CTB at 72 h after ischemia. In the peripheral blood, CTB increased Treg cells and suppressed γδT cells at 24 h after ischemia. And then at 72 h after ischemia, it increased Treg cells but did not impact γδT cells. CTB had no effect on cytokines, transcription factors, infiltrating γδT cells, and Treg cells in the brain of shams. In the peripheral blood of shams, CTB increased Treg cells at both 24 and 72 h, while it did not affect γδT cells. CTB decreased neurologic impairment and tissue injury after cerebral ischemia via its immunomodulatory functions, including inhibiting microglia/macrophage activation, suppressing γδT cells, and inducing production of Treg cells, thus regulating the secretion of related cytokines. Suppression of NF-kB and ERK1/2 pathways is involved in the neuroprotective mechanism of CTB.