The MYD88-independent pathway is not mobilized in human neutrophils stimulated via TLR4
The MYD88-independent pathway is not mobilized in human neutrophils stimulated via TLR4
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DOI：
10.4049/jimmunol.178.11.7344
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发表时间：
2007-06-01
影响因子：
4.4
通讯作者：
Cassatella, Marco A.
中科院分区：
文献类型：
--
作者：
Tamassia, Nicola;Le Moigne, Vincent;Cassatella, Marco A.
LPS通过TLR 4激活MyD 88依赖性和非依赖性信号传导，但每个级联在不同细胞类型中的作用程度仍不清楚。这促使我们重新审视CXCL 10产生的有趣问题，我们先前表明，在用LPS和IFN-γ刺激的中性粒细胞中，CXCL 10是可诱导的，但与其他骨髓细胞相反，单独使用任何一种刺激都不行。我们现在报告，在中性粒细胞中，MyD 88非依赖性通路不被LPS激活。事实上，微阵列和实时PCR实验表明，与单核细胞相反，在LPS处理的中性粒细胞中，IFN β和IFN β依赖性基因（包括CXCL 10）都不是可诱导的。对LPS不能促进中性粒细胞中IFN β 6表达的进一步研究表明，调节IFN β增强体的转录因子，如IFN-调节因子-3和AP-1，在LPS处理的中性粒细胞中不被激活，如缺乏二聚化、核转位、共聚焦显微镜和与DNA的诱导性结合所揭示的。此外，我们发现，上游TANK结合激酶-1在中性粒细胞中不被LPS激活。在分化为粒细胞然后用LPS刺激的髓性白血病HL 60细胞中也观察到IFN β/CXCL 10 mRNA表达和IFN-调节因子3活化的缺乏，表明中性粒细胞不能活化MyD 88-非依赖性途径代表其终末成熟的特征。这些结果确定了TLR 4下游的两个信号通路在炎症和免疫反应的关键细胞组分中的断开激活，并帮助我们更好地理解中性粒细胞在宿主防御非病毒感染中的原始作用。
LPS activates both MyD88-dependent and -independent signaling via TLR4, but the extent to which each cascade is operative in different cell types remains unclear. This prompted us to revisit the intriguing issue of CXCL10 production, which we previously showed to be inducible in neutrophils stimulated with LPS and IFN-gamma but not with either stimulus alone, contrary to other myeloid cells. We now report that in neutrophils the MyD88-independent pathway is not activated by LPS. Indeed, microarray and real-time PCR experiments showed that neither IFN beta nor IFN beta-dependent genes (including CXCL10) are inducible in LPStreated neutrophils, in contrast to monocytes. Further investigation into the inability of LPS to promote IFN,6 expression in neutrophils revealed that the transcription factors regulating the IFN beta enhanceosome, such as IFN-regulatory factor-3 and AP-1, are not activated in LPS-treated neutrophils as revealed by lack of dimerization, nuclear translocation, confocal microscopy, and inducible binding to DNA. Moreover, we show that the upstream TANK-binding kinase-1 is not activated by LPS in nentrophils. A lack of IFN beta/CXCLIO mRNA expression and IFN-regulatory factor 3 activation was also observed in myeloid leukemia HL60 cells differentiated to granulocytes and then stimulated with LPS, indicating that the inability of neutrophils to activate the MyD88-independent pathway represents a feature of their terminal maturation. These results identify a disconnected activation of the two signaling pathways downstream of TLR4 in key cellular components of the inflammatory and immune responses and help us to better understand the primordial role of neutrophils in host defense against nonviral infections.