TAK1 inhibition prevents the development of autoimmune diabetes in NOD mice.
TAK1 inhibition prevents the development of autoimmune diabetes in NOD mice.
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DOI：
10.1038/srep14593
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发表时间：
2015-10-13
影响因子：
4.6
通讯作者：
Xiang M
中科院分区：
文献类型：
--
作者：
Cao H;Lu J;Du J;Xia F;Wei S;Liu X;Liu T;Liu Y;Xiang M
转化生长因子-β激活的蛋白激酶-1(Tak1，MAP3k7)是丝裂原活化蛋白激酶(MAP3K)家族的成员，在先天免疫和获得性免疫反应中起重要作用。我们推测，阻断TAK1会影响非肥胖糖尿病(NOD)小鼠的自身免疫性糖尿病。TAK1抑制剂5Z-7-oxozeaenol(OZ)可降低自发性和加速性(环磷酰胺诱导的)NOD小鼠自身免疫性糖尿病的发生率并延缓其发病。Oz还能减轻胰岛炎症，保护胰岛功能，增加α-1抗胰蛋白酶的表达，并严重抑制免疫器官和胰腺组织中的NF-κB和JNKAP-1信号通路。重要的是，OZ抑制Tak1诱导T淋巴细胞培养上清液中Th1型细胞因子向Th2型细胞因子的转变，并增加转化生长因子β1的产生。全身性TAK1抑制可诱导低表达MHC-II和CD86的未成熟DC，抑制DC介导的同种异体MLR中T细胞的增殖，并抑制DC悬液中细胞因子IL-12p70的产生。结果表明，用OZ抑制TAK1与NOD小鼠发生自身免疫性糖尿病的频率较低有关。因此，抑制TAK1对NOD小鼠的净作用似乎是保护性的，而不是增强疾病。针对NOD小鼠TAK1的策略可能被证明对治疗自身免疫性糖尿病总体上有用。
Transforming growth factor-β activated kinase-1 (TAK1, Map3k7), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, is essential in innate and adaptive immune responses. We postulated that blockade of TAK1 would affect autoimmune diabetes in non-obese diabetic (NOD) mice. Administration of 5Z-7-oxozeaenol (OZ), a TAK1 inhibitor, decreased the incidence and delayed the onset of autoimmune diabetes in both spontaneous and accelerated (cyclophosphamide-induced) experimental NOD mice. OZ also reduced insulitis, preserved islet function, increased the expression of α1- antitrypsin (AAT), and severely inhibited NF-κB and JNK/AP-1 signaling pathways in immune organs and pancreatic tissues. Importantly, TAK1 inhibition by OZ elicited a Th1 to Th2 cytokine shift, and increased TGF-β1 production in cultured T lymphocytes supernatants. Systemic TAK1 inhibition induced immature DCs with lower expressions of MHC-II and CD86, attenuated DC-mediated T cell proliferation in allogeneic MLR, and production of cytokine IL-12p70 in DCs suspensions. The results indicate that TAK1 inhibition with OZ was associated with a lower frequency of autoimmune diabetes in NOD mice. The net effect of TAK1 inhibition in NOD mice therefore appears to be protective rather than disease-enhancing. Strategies targeting TAK1 specifically in NOD mice might prove useful for the treatment of autoimmune diabetes in general.