Max-Planck-Institute of Immunobiology and Epigenetics, D-79108 Freiburg, Germany.
J Immunol. 2011 May 1;186(9):5478-88. doi: 10.4049/jimmunol.1000458. Epub 2011 Mar 25.
In macrophages, two signaling pathways, dependent on MyD88 or TIR domain-containing adaptor-inducing IFN-β (TRIF) signaling, emanate from the LPS receptor TLR4/MD-2. In this study, we show that in murine bone marrow-derived mast cells (BMMCs), only the MyD88-dependent pathway is activated by LPS. The TRIF signaling branch leading both to NF-κB activation and enhanced proinflammatory cytokine production, as well as to IRF3 activation and subsequent IFN-β production, is absent in LPS-stimulated BMMCs. IRF3 activation is also absent in peritoneal mast cells from LPS-injected mice. We observed strongly diminished TRAM expression in BMMCs, but overexpression of TRAM only moderately enhanced IL-6 and did not boost IFN-β responses to LPS in these cells. A combination of very low levels of TRAM and TLR4/MD-2 with the known absence of membrane-bound CD14 are expected to contribute to the defective TRIF signaling in mast cells. We also show that, unlike in macrophages, in BMMCs the TRIF-dependent and -independent IFN-αβ responses to other recognized IFN inducers (dsRNA, adenovirus, and B-DNA) are absent. These results show how the response to the same microbial ligand using the same receptor can be regulated in different cell types of the innate immune system.
在巨噬细胞中，两种信号通路依赖于 MyD88 或 TIR 结构域包含衔接子诱导 IFN-β（TRIF）信号，从 LPS 受体 TLR4/MD-2 发出。在这项研究中，我们表明在鼠骨髓来源的肥大细胞（BMMC）中，只有 LPS 激活 MyD88 依赖性途径。TRIF 信号分支导致 NF-κB 激活和增强的促炎细胞因子产生，以及 IRF3 激活和随后的 IFN-β产生，在 LPS 刺激的 BMMC 中缺失。IRF3 激活也在 LPS 注射小鼠的腹腔肥大细胞中缺失。我们观察到 BMMC 中 TRAM 的表达明显降低，但 TRAM 的过表达仅适度增强了 IL-6，并且不能增强这些细胞对 LPS 的 IFN-β反应。TRAM 和 TLR4/MD-2 的极低水平与已知不存在膜结合 CD14 相结合，预计会导致肥大细胞中 TRIF 信号的缺陷。我们还表明，与巨噬细胞不同，在 BMMC 中，TRIF 依赖性和非依赖性 IFN-αβ 对其他公认的 IFN 诱导剂（dsRNA、腺病毒和 B-DNA）的反应缺失。这些结果表明，相同的先天免疫系统细胞类型如何调节对同一微生物配体使用相同受体的反应。
