Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems

Lundberg, Anna M, Drexler, Stefan K, Monaco, Claudia, Williams, Lynn M, Sacre, Sandra M, Feldmann, Marc and Foxwell, Brian M (2007) Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems. Blood, 110 (9). pp. 3245-3252. ISSN 0006-4971

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Abstract

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 (MØs), 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 MØs failed to produce the proinflammatory cytokines TNFalpha and IL-6. Unexpectedly, TNFalpha was found secreted by TLR3-stimulated RA-SF. Furthermore, TLR3 stimulation did not activate NFkappaB, MAPKs, or IRF-3 in DCs and MØs, 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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: Q Science
R Medicine
Depositing User: Sandra Sacre
Date Deposited: 01 Nov 2012 14:34
Last Modified: 05 Oct 2017 18:27
URI: http://sro.sussex.ac.uk/id/eprint/41161
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