Parker Lisa C, Whyte Moira K B, Vogel Stefanie N, Dower Steven K, Sabroe Ian
Section of Functional Genomics, Division of Genomic Medicine, University of Sheffield, Sheffield, United Kingdom.
J Immunol. 2004 Apr 15;172(8):4977-86. doi: 10.4049/jimmunol.172.8.4977.
Interactions between proinflammatory and cell maturation signals, and the pathways that regulate leukocyte migration, are of fundamental importance in controlling trafficking and recruitment of leukocytes during the processes of innate and adaptive immunity. We have investigated the molecular mechanisms by which selective Toll-like receptor (TLR)2 and TLR4 agonists regulate expression of CCR1 and CCR2 on primary human monocytes and THP-1 cells, a human monocytic cell line. We found that activation of either TLR2 (by Pam(3)CysSerLys(4)) or TLR4 (by purified LPS) resulted in down-modulation of both CCR1 and CCR2. Further investigation of TLR-induced down-modulation of CCR1 revealed differences in the signaling pathways activated, and chemokines generated, via the two TLR agonists. TLR2 activation caused slower induction of the NF-kappa B and mitogen-activated protein kinase signaling pathways and yet a much enhanced and prolonged macrophage-inflammatory protein 1 alpha (CC chemokine ligand 3) protein production, when compared with TLR4 stimulation. Enhanced macrophage-inflammatory protein 1 alpha production may contribute to the prolonged down-regulation of CCR1 cell surface expression observed in response to the TLR2 agonist, as preventing chemokine generation with the protein synthesis inhibitor cycloheximide, or CCR1 signaling with the receptor antagonist UCB35625, abolished TLR2- and TLR4-induced CCR1 down-modulation. This result suggests an autocrine pathway, whereby TLR activation can induce chemokine production, which then leads to homologous down-regulation of the cognate receptors. This work provides further insights into the mechanisms that regulate leukocyte recruitment and trafficking during TLR-induced inflammatory responses.
促炎信号与细胞成熟信号之间的相互作用，以及调节白细胞迁移的途径，对于在固有免疫和适应性免疫过程中控制白细胞的运输和募集至关重要。我们研究了选择性Toll样受体（TLR）2和TLR4激动剂调节原代人单核细胞和人单核细胞系THP-1细胞上CCR1和CCR2表达的分子机制。我们发现，激活TLR2（通过Pam(3)CysSerLys(4)）或TLR4（通过纯化的LPS）都会导致CCR1和CCR2的下调。对TLR诱导的CCR1下调的进一步研究揭示了通过两种TLR激动剂激活的信号通路以及产生的趋化因子存在差异。与TLR4刺激相比，TLR2激活导致NF-κB和丝裂原活化蛋白激酶信号通路的诱导较慢，但巨噬细胞炎性蛋白1α（CC趋化因子配体3）的蛋白产生却大大增强且持续时间延长。增强的巨噬细胞炎性蛋白1α产生可能有助于解释在对TLR2激动剂的反应中观察到的CCR1细胞表面表达的长期下调，因为用蛋白质合成抑制剂环己酰亚胺阻止趋化因子产生，或用受体拮抗剂UCB35625阻断CCR1信号传导，都消除了TLR2和TLR4诱导的CCR1下调。这一结果表明存在一种自分泌途径，即TLR激活可诱导趋化因子产生，进而导致同源受体的同源下调。这项工作为TLR诱导的炎症反应过程中调节白细胞募集和运输的机制提供了进一步的见解。
