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.
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology, and Medicine, 1 Aspenlea Road, Hammersmith, London, United Kingdom.
Anna M
AM
Lundberg
Stefan K
SK
Drexler
Claudia
C
Monaco
Lynn M
LM
Williams
Sandra M
SM
Sacre
Marc
M
Feldmann
Brian M
BM
Foxwell
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