FcγRIII-mediated production of TNF-α induces immune complex alveolitis independently of CXC chemokine generation
FcγRIII-mediated production of TNF-α induces immune complex alveolitis independently of CXC chemokine generation
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DOI：
10.4049/jimmunol.166.8.5193
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发表时间：
2001-04-15
影响因子：
4.4
通讯作者：
Gessner, JE
中科院分区：
文献类型：
--
作者：
Chouchakova, N;Skokowa, J;Gessner, JE
我们最近证明了C5 aR和Fe γ RIII在小鼠IgG免疫复合物介导的炎症的起始中的共显性作用。在这项研究中，我们研究了Fc γ RIII在体内实验性过敏性肺炎/肺泡炎期间产生几种细胞因子的相对贡献。在C57 BL/6小鼠中诱导免疫复合物-肺泡炎导致嗜中性粒细胞大量积聚到肺中，并增强支气管肺泡灌洗液中的趋化活性，伴随促炎细胞因子TNF-α和IL-1 β以及ELR-CXC趋化因子巨噬细胞炎性蛋白-2（MIP-2）和尼古丁诱导的嗜中性粒细胞趋化因子（KC）的产生增加。Fc γ RIII缺陷型C57 BL/6小鼠（Fc γ RIII-/-）由于TNF-α、IL-1 β和MIP-2的产生减少而显示炎症反应显著降低。在缺乏TNF-α I类受体（TNF-α RI-/-）或用中和性抗TNF-α mAb处理的C57 BL/6小鼠中获得的结果证明TNF-α对介导IL-1 β释放、中性粒细胞流入和出血具有重要作用。令人惊讶的是，MIP-2和KC趋化因子水平在TNF-α RI-/-小鼠或TNF-α功能抑制后基本上不受影响。这些数据表明，在免疫复合物肺泡炎中，Fc γ RIII的活化可诱导不同的下游效应子途径，其中TNF-α独立于CXC趋化因子起作用以触发C57 BL/6小鼠中的炎症反应。
We recently demonstrated a codominant role of C5aR and Fe gamma RIII in the initiation of IgG immune complex-mediated inflammation in mice. In this study, we investigated the relative contribution of Fc gamma RIII in the generation of several cytokines during experimental hypersensitivity pneumonitis/alveolitis in vivo. Induction of immune complex-alveolitis in C57BL/6 mice resulted in strong accumulation of neutrophils into the lung and enhanced chemotactic activity within bronchoalveolar lavage fluid accompanied by an increased production of the proinflammatory cytokines TNF-alpha and IL-1 beta as well as the ELR-CXC chemokines macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC). Fc gamma RIII-deficient C57BL/6 mice (Fc gamma RIII-/-) showed a marked reduction of the inflammatory response due to decreased production of TNF-alpha, IL-1 beta, and MIP-2. Results obtained in C57BL/6 mice either lacking the TNF-a class I receptor (TNF-alpha RI-/-) or treated with neutralizing anti-TNF-alpha mAb demonstrated an essential contribution of TNF-alpha for mediating IL-1 beta release, neutrophil influx, and hemorrhage. Surprisingly, MIP-2 and KC chemokine levels remained largely unaffected in TNF-alpha RI-/- mice or after functional inhibition of TNF-alpha. These data suggest that in immune complex alveolitis, the activation of Fc gamma RIII may induce divergent downstream effector pathways with TNF-a acting independently of CXC chemokines to trigger the inflammatory response in C57BL/6 mice.