Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems.
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.
Lundberg
Anna M
AM
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology, and Medicine, 1 Aspenlea Road, Hammersmith, London, United Kingdom.
Drexler
Stefan K
SK
Monaco
Claudia
C
Williams
Lynn M
LM
Sacre
Sandra M
SM
Feldmann
Marc
M
Foxwell
Brian M
BM
D000818:Animals; D018929:Cell Culture Techniques; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D011070:Poly I-C / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D013045:Species Specificity; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
D016207:Cytokines; D018836:Inflammation Mediators; D051196:Toll-Like Receptor 3; D011070:Poly I-C