Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses
Fractalkine (CX3CL1) as an amplification circuit of polarized Th1 responses
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DOI：
10.1172/jci11517
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发表时间：
2001-05-01
影响因子：
15.9
通讯作者：
Mantovani, A
中科院分区：
文献类型：
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作者：
Fraticelli, P;Sironi, M;Mantovani, A
Fractalkine（FKN，CX 3CL 1）是一种膜结合的CX 3C趋化因子，由血管内皮细胞（EC）中的主要促炎信号诱导。在这里，我们研究了FKN在极化Th 1或Th 2反应中的作用。促炎信号，包括LPS、IL-1、TNF和CD 40配体，诱导FKN，IFN-γ也诱导FKN，IFN-γ与TNF具有协同活性。IL-4和IL-13不刺激FKN的表达，并显著降低TNF和IFN-γ的诱导作用。TNF单独或与IFN-γ组合也诱导可溶性FKN的释放，其被IL-4和IL-13抑制。鉴于FKN受控制极化反应的主要细胞因子的这种差异调节，我们分析了FKN与自然杀伤（NK）细胞和极化T细胞群体的相互作用。NK细胞表达高水平的FKN受体CX 3CR 1，并对FKN产生应答。CX 3CR 1在Th 1细胞中的表达明显高于Th 2细胞。Th 1细胞对FKN有反应，而Th 2细胞无反应。通过免疫组化，FKN在银屑病（一种Th 1型为主的皮肤病）的内皮细胞上表达，但在Th 2型驱动的特应性皮炎中不表达。类似地，结核分枝杆菌肉芽肿性淋巴结炎的EC，而不是反应性淋巴结增生或Castelman病的EC，显示免疫反应性FKN。这些结果表明，FKN在内皮细胞中的调节表达参与了极化I型反应的放大电路。
Fractalkine (FKN, CX3CL1) is a membrane-bound CX3C chemokine induced by primary proinflammatory signals in vascular endothelial cells (ECs). Here we examined the role of FKN in polarized Th1 or Th2 responses. Proinflammatory signals, including LPS, IL-1, TNF, and CD40 ligand, induced FKN, as did IFN-gamma, which had synergistic activity with TNF. IL-4 and IL-13 did not stimulate the expression of FKN and markedly reduced induction by TNF and IFN-gamma. TNF alone or combined with IFN-gamma also induced release of soluble FKN, which was inhibited by IL-4 and IL-13. In light of this differential regulation of FKN by the master cytokines that control polarized responses, we analyzed the interaction of FKN with natural killer (NK) cells and polarized T-cell populations. NK cells expressed high levels of the FKN receptor CX3CR1 and responded to FKN. CX3CR1 was preferentially expressed in Th1 compared with Th2 cells. Th1 but not Th2 cells responded to FKN. By immunohistochemistry, FKN was expressed on ECs in psoriasis, a Th1-dominated skin disorder, but not in Th2-driven atopic dermatitis. Similarly, ECs in Mycobacterium tuberculosis granulomatous lymphadenitis, but not those in reactive lymph node hyperplasia or in Castelman's disease, showed immunoreactive FKN. These results indicate that regulated expression of FKN in ECs participates in an amplification circuit of polarized type I responses.