Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells:: a phenomenon absent from murine cell systems
Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells:: a phenomenon absent from murine cell systems
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DOI：
10.1182/blood-2007-02-072934
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发表时间：
2007-11-01
期刊：
影响因子：
20.3
通讯作者：
Foxwell, Brian M.
中科院分区：
文献类型：
--
作者：
Lundberg, Anna M.;Drexler, Stefan K.;Foxwell, Brian M.
TLR 3识别双链RNA，这是一种与病毒感染相关的产物。TLR 3诱导机制的许多细节已经出现在基因靶向小鼠或转化细胞系的抑制研究中。然而，在人类免疫细胞或来自疾病组织的细胞中激活的途径还不太清楚。我们已经研究了TLR 3诱导的先天免疫系统的人原代细胞的机制，包括树突状细胞（DC）、巨噬细胞（MO）、内皮细胞（EC）和从类风湿性关节炎关节组织（RA-SF）分离的滑膜成纤维细胞。在这里，我们报告说，虽然这些细胞都表达TLR 3，但它们对TLR 3刺激的反应有很大差异。关键的抗病毒反应趋化因子IP-10由所有细胞类型产生，而DC和MO不能产生促炎细胞因子TNF α和IL-6。出乎意料的是，发现TNFa由TLR 3刺激的RA-SF分泌。此外，TLR 3刺激不能激活DC和MO中的NF κ B B、MAPK或IRF-3，但能够在EC和RA-SF中激活。这些发现是人类细胞特有的，从而揭示了以前没有预料到的复杂性。这是第一次报道这种细胞类型和物种特异性反应的任何TLR刺激，并有助于解释相关的炎症性疾病和人类炎症的小鼠模型的重要困难。
TLR3 recognizes double-stranded RNA, a product associated with viral infections. Many details of TLR3-induced mechanisms have emerged from gene-targeted mice or inhibition studies in transformed cell lines. However, the pathways activated in human immune cells or cells from disease tissue are less well understood. We have investigated TLR3-induced mechanisms of human primary cells of the innate immune system, including dendritic cells (DCs), macrophages (MOs), endothelial cells (ECs), and synovial fibroblasts isolated from rheumatoid arthritis joint tissue (RA-SFs). Here, we report that while these cells all express TLR3, they differ substantially in their response to TLR3 stimulation. The key antiviral response chemokine IP-10 was produced by all cell types, while DCs and MOs failed to produce the proinflammatory cytokines TNF alpha and IL-6. Unexpectedly, TNFa was found secreted by TLR3-stimulated RA-SF. Furthermore, TLR3 stimulation did not activate NF kappa B, MAPKs, or IRF-3 in DCs and MOs, but was able to do so in ECs and RA-SF. These findings were specific for human cells, thereby revealing a complexity not previously expected. This is the first report of such cell type- and species-specific response for any TLR stimulation and helps to explain important difficulties in correlating murine models of inflammatory diseases and human inflammation.