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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3245-3252. Prepublished online as a Blood First Edition Paper on July 27, 2007; DOI 10.1182/blood-2007-02-072934. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-02-072934v1 110/9/3245    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lundberg, A. M. Articles by Foxwell, B. M. Search for Related Content PubMed PubMed Citation Articles by Lundberg, A. M. Articles by Foxwell, B. M. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems Anna M. Lundberg1, Stefan K. Drexler1, Claudia Monaco1, Lynn M. Williams1, Sandra M. Sacre1, Marc Feldmann1, and Brian M. Foxwell1 1 Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology, and Medicine, London, United Kingdom 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 TNF and IL-6. Unexpectedly, TNF was found secreted by TLR3-stimulated RA-SF. Furthermore, TLR3 stimulation did not activate NFB, 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Jiang, Y. Ke, D. Sun, Y. Wang, H. J. Kaplan, and H. Shao Regulatory Role of TLR Ligands on the Activation of Autoreactive T Cells by Retinal Astrocytes Invest. Ophthalmol. Vis. Sci., October 1, 2009; 50(10): 4769 - 4776. [Abstract] [Full Text] [PDF] C. K. Holm, C. C. Petersen, M. Hvid, L. Petersen, S. R. Paludan, B. Deleuran, and M. Hokland TLR3 Ligand Polyinosinic:Polycytidylic Acid Induces IL-17A and IL-21 Synthesis in Human Th Cells J. Immunol., October 1, 2009; 183(7): 4422 - 4431. [Abstract] [Full Text] [PDF] W. G. Cho, R. J. C. Albuquerque, M. E. Kleinman, V. Tarallo, A. Greco, M. Nozaki, M. G. Green, J. Z. Baffi, B. K. Ambati, M. 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Simmonds, L. Williams, M. Feldmann, F. M. Brennan, and B. M. Foxwell Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures J. Immunol., December 1, 2008; 181(11): 8002 - 8009. [Abstract] [Full Text] [PDF] T. Yoshizawa, D. Hammaker, S. E. Sweeney, D. L. Boyle, and G. S. Firestein Synoviocyte Innate Immune Responses: I. Differential Regulation of Interferon Responses and the JNK Pathway by MAPK Kinases J. Immunol., September 1, 2008; 181(5): 3252 - 3258. [Abstract] [Full Text] [PDF] T. Reimer, M. Brcic, M. Schweizer, and T. W. Jungi poly(I:C) and LPS induce distinct IRF3 and NF-{kappa}B signaling during type-I IFN and TNF responses in human macrophages J. Leukoc. Biol., May 1, 2008; 83(5): 1249 - 1257. [Abstract] [Full Text] [PDF] R. E. Simmonds and B. M. Foxwell Signalling, inflammation and arthritis: NF-{kappa}B and its relevance to arthritis and inflammation Rheumatology, May 1, 2008; 47(5): 584 - 590. [Abstract] [Full Text] [PDF]

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