Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40
Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40
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DOI：
10.1093/emboj/cdg386
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发表时间：
2003-08-01
期刊：
影响因子：
11.4
通讯作者：
Tsichlis, PN
中科院分区：
文献类型：
--
作者：
Eliopoulos, AG;Wang, CC;Tsichlis, PN
来自Tpl 2敲除（Tpl 2（-/-））小鼠的巨噬细胞表现出脂多糖（LPS）对ERK活化的缺陷。这损害了肿瘤坏死因子α（TNF-α）mRNA的核质转运，并阻止LPS诱导TNF-α。结果，Tpl 2（-/-）小鼠对LPS/d-半乳糖胺诱导的休克具有抗性。我们证明了Tp 12对于由TNF受体超家族的成员如CD 40和TNF受体1转导的ERK信号是必需的。因此，ERK活化在用激动性CD 40抗体或TNF-α刺激的Tp 12（-/-）B细胞和巨噬细胞中受损，而其它促分裂原活化蛋白激酶如JNK和p38的诱导以及NF-κ B的活化不受影响。Tpl 2响应于CD 40刺激被募集至CD 40/TRAF 6复合物。此外，TRAF 6在过表达时激活ERK，但在Tp 12（-/-）细胞中不能这样做。由Tp 12失活导致的选择性信号传导缺陷使我们能够证明CD 40介导的ERK活化有助于免疫球蛋白产生，但对于B细胞增殖不是必需的。
Macrophages from Tpl2 knockout (Tpl2(-/-)) mice exhibit a defect in ERK activation by lipopolysaccharide (LPS). This impairs the nucleocytoplasmic transport of the tumor necrosis factor alpha (TNF-alpha) mRNA and prevents the induction of TNF-alpha by LPS. As a result, Tpl2(-/-) mice are resistant to LPS/d-galactosamine-induced shock. We demonstrate that Tpl2 is essential for ERK signals transduced by members of the TNF receptor superfamily, such as CD40 and the TNF receptor 1. Thus, ERK activation was impaired in Tpl2(-/-) B cells and macrophages stimulated with agonistic CD40 antibody or TNF-alpha, whereas the induction of other mitogen-activated protein kinases, such as JNK and p38, and the activation of NF-kappaB were unaffected. Tpl2 was recruited to a CD40/TRAF6 complex in response to CD40 stimulation. Moreover, TRAF6, which when overexpressed activates ERK, failed to do so in Tpl2(-/-) cells. The selective signaling defect resulting from the inactivation of Tpl2 allowed us to demonstrate that CD40-mediated ERK activation contributes to immunoglobulin production but is not essential for B-cell proliferation.