期刊
BLOOD
卷 110, 期 9, 页码 3245-3252出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-02-072934
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资金
- Medical Research Council [G0700128] Funding Source: researchfish
- MRC [G0700128] Funding Source: UKRI
- Medical Research Council [G0700128] Funding Source: Medline
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.
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