Caspase-4 interacts with TNF receptor-associated factor 6 and mediates lipopolysaccharide-induced NF-κB-dependent production of IL-8 and CC chemokine ligand 4 (macrophage-inflammatory protein-1β)
Caspase-4 interacts with TNF receptor-associated factor 6 and mediates lipopolysaccharide-induced NF-κB-dependent production of IL-8 and CC chemokine ligand 4 (macrophage-inflammatory protein-1β)
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DOI：
10.4049/jimmunol.179.12.8480
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发表时间：
2007-12-15
影响因子：
4.4
通讯作者：
Porter, Alan G.
中科院分区：
文献类型：
--
作者：
Lakshmanan, Umayal;Porter, Alan G.
人胱天蛋白酶-4没有相应的小鼠直系同源物。半胱天冬酶-4福尔斯属于“炎性半胱天冬酶”类别，与人半胱天冬酶I和5以及小鼠半胱天冬酶1、11和12同源。为了阐明半胱天冬酶-4的功能，我们产生了半胱天冬酶-4缺陷型人THP 1单核细胞系，该细胞系表现出显著减少的LPS诱导的几种趋化因子和细胞因子的分泌，包括IL-8（CXCL 8）、CCL 4（巨噬细胞炎性蛋白-1 β）、CCL 20（巨噬细胞炎性蛋白-3 α）和IL-1 β。编码这些细胞因子的mRNA的LPS诱导的表达在caspase-4缺陷克隆中相应地减少。由于特异性NF-κ B抑制剂阻断LPS诱导的THP 1细胞中IL-8和CCL 4 mRNA表达以及IL-8和CCL 4分泌，我们研究了caspase-4在NF-κ B信号传导中的作用。LPS诱导的NF-κ B核转位和活化在所有caspase-4缺陷克隆中被抑制。LPS刺激导致内源性caspase-4和TNFR相关因子6（TRAF 6）通过TRAF 6结合基序（PPESGE）的相互作用，这是我们在caspase-4中发现的。caspase-4中该位点的突变导致TRAF 6-caspase-4相互作用的丧失。已知类似的TRAF 6结合基序对于TRAF 6与其他分子（包括半胱天冬酶-8）的相互作用以及介导各种免疫和非免疫细胞类型中的NF-κ B活化在功能上是重要的。我们的数据表明，TRAF 6-caspase-4的相互作用，由LPS触发，导致NF-κ B依赖性转录上调和分泌的重要细胞因子和趋化因子的先天免疫信号在人单核细胞。
Human caspase-4 does not have a corresponding mouse ortholog. Caspase-4 falls within the class of "inflammatory caspases," being homologous with human caspases I and 5 and mouse caspases 1, 11, and 12. To address the function of caspase-4, we generated caspase-4-deficient human THP1 monocytic cell lines which exhibited substantially reduced LPS-induced secretion of several chemokines and cytokines, including IL-8 (CXCL8), CCL4 (macrophage-inflammatory protein-1 beta), CCL20 (macrophageinflammatory protein-3 alpha), and IL-1 beta. The LPS-induced expression of the mRNAs encoding these cytokines was correspondingly reduced in the caspase-4-deficient clones. Because a specific NF-kappa B inhibitor blocked LPS-induced IL-8 and CCL4 mRNA expression as well as IL-8 and CCL4 secretion in THP1 cells, we investigated the role of caspase-4 in NF-kappa B signaling. LPS-induced NF-kappa B nuclear translocation and activation were inhibited in all caspase-4-deficient clones. LPS stimulation led to the interaction of endogenous caspase-4 and TNFR-associated factor 6 (TRAF6) via a TRAF6-binding motif (PPESGE), which we identified in caspase-4. Mutation of this site in caspase-4 resulted in the loss of the TRAF6-caspase-4 interaction. Similar TRAF6-binding motifs are known to be functionally important for TRAF6 interactions with other molecules including caspase-8, and for mediating NF-kappa B activation in various immune and nonimmune cell types. Our data suggest that the TRAF6-caspase-4 interaction, triggered by LPS, leads to NF-kappa B-dependent transcriptional up-regulation and secretion of important cytokines and chemokines in innate immune signaling in human monocytic cells.