Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NTF-κB activation in dendritic cells
Apoptotic cells induce Mer tyrosine kinase-dependent blockade of NTF-κB activation in dendritic cells
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DOI：
10.1182/blood-2006-04-017368
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发表时间：
2007-01-15
期刊：
影响因子：
20.3
通讯作者：
Tisch, Roland M.
中科院分区：
文献类型：
--
作者：
Sen, Pradip;Wallet, Mark A.;Tisch, Roland M.
树突状细胞（Dendritic cells，DCs）在维持机体免疫稳态和自身免疫耐受中起重要作用。致耐受性DC可以通过与凋亡细胞（AC）相遇并随后抑制成熟和效应器功能来建立。参与AC诱导的DC抑制的受体和信号通路尚未确定。我们证明，用凋亡而非坏死细胞预处理抑制I κ B激酶（IKK）和下游NF-κ B的活化。值得注意的是，AC的受体酪氨酸激酶Mer（MerTK）结合是介导该效应所必需的。缺乏MerTK表达（MerTK（KD））或用阻断MerTK特异性抗体（Ab）处理的单核细胞衍生的DC对AC诱导的抑制具有抗性，并继续激活NF-κ B并分泌促炎细胞因子。阻断磷脂酰肌醇3-激酶（PI 3 K）/AKT通路的MerTK活化可防止AC诱导的抑制。这些结果表明MerTK介导的PI 3 K/AKT和NF-κ B途径调节在AC诱导的单核细胞来源DC抑制中发挥着重要作用。
Dendritic cells (DCs) play a key role in immune homeostasis and maintenance of self-tolerance. Tolerogenic DCs can be established by an encounter with apoptotic cells (ACs) and subsequent inhibition of maturation and effector functions. The receptor(s) and signaling pathway(s) involved in AC-induced inhibition of DCs have yet to be defined. We demonstrate that pretreatment with apoptotic but not necrotic cells inhibits activation of I kappa B kinase (IKK) and downstream NF-kappa B. Notably, receptor tyrosine kinase Mer (MerTK) binding of ACs is required for mediating this effect. Monocyte-derived DCs lacking MerTK expression (MerTK(KD)) or treated with blocking MerTK-specific antibodies (Abs) are resistant to AC-induced inhibition and continue to activate NF-kappa B and secrete proinflammatory cytokines. Blocking MerTK activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway prevents AC-induced inhibition. These results demonstrate an essential role for MerTK-mediated regulation of the PI3K/AKT and NF-kappa B pathways in AC-induced inhibition of monocytederived DCs.