TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages
TNF receptor-associated factor 6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages
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DOI：
10.4049/jimmunol.174.2.1081
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发表时间：
2005-01-15
影响因子：
4.4
通讯作者：
Suttles, J
中科院分区：
文献类型：
--
作者：
Mukundan, L;Bishop, GA;Suttles, J
CD 40及其配体CD 154之间的相互作用已被证明在炎性疾病的发生和维持中起作用。CD 40对单核细胞和巨噬细胞炎性细胞因子产生信号的能力促成了这一过程。我们已经表明，这一事件是依赖于Src家族酪氨酸激酶活性和随后的ERK 1/2的激活。为了解决肿瘤坏死因子相关因子（TRAF）家族成员在促进这一信号通路中的作用，我们用野生型人CD 40或含有破坏的TRAY结合位点的CD 40转染了CD 40缺陷型巨噬细胞系。野生型CD 40或不能结合TRAF 2/3/5的CD 40突变体的连接导致炎性细胞因子产生的刺激。然而，缺乏功能性TRAF 6结合位点的CD 40突变体的连接并不启动炎性细胞因子的产生，并且发现该突变体在CD 40介导的ERK 1/2活化以及IkappaB激酶（IKK）和NF-κ B中存在缺陷。同样，将显性阴性TRAF 6导入野生型（CD 40（+））巨噬细胞系导致CD 40介导的炎性细胞因子合成诱导的消除。最后，用对应于CD 40的TRAF 6结合基序的细胞可渗透肽处理单核细胞抑制了CD 40对ERK 1/2、IKK和炎性细胞因子产生的激活。这些数据表明TRAF 6在单核细胞和巨噬细胞中作为Src/ERK 1/2和IKK/NF-κ B促炎信号通路的关键衔接子。
The interaction between CD40 and its ligand, CD154, has been shown to play a role in the onset and maintenance of inflammatory disease. Contributing to this process is the ability of CD40 to signal monocyte and rnacrophage inflammatory cytokine production. We have shown that this event is dependent on Src family tyrosine kinase activity and the subsequent activation of ERK1/2. To address the role of TNFR-associated factor (TRAF) family members in facilitating this signaling pathway, we transfected a CD40-deficient macrophage cell line with wild-type human CD40, or with CD40 containing disrupted TRAY binding sites. Ligation of either wild-type CD40, or a CD40 mutant unable to bind TRAF2/3/5, resulted in the stimulation of inflammatory cytokine production. However, ligation of a CD40 mutant lacking a functional TRAF6 binding site did not initiate inflammatory cytokine production, and this mutant was found to be defective in CD40-mediated activation of ERK1/2, as well as IkappaB kinase (IKK) and NF-kappaB. Likewise, introduction of a dominant-negative TRAF6 into a wild-type (CD40(+)) macrophage cell line resulted in abrogation of CD40-mediated induction of inflammatory cytokine synthesis. Finally, treatment of monocytes with a cell-permeable peptide corresponding to the TRAF6-binding motif of CD40 inhibited CD40 activation of ERK1/2, IKK, and inflammatory cytokine production. These data demonstrate that TRAF6 acts as a critical adapter of both the Src/ERK1/2 and IKK/NF-kappaB proinflammatory signaling pathways in monocytes and macrophages.