SEARCH:   Advanced

Blood, 15 March 2004, Vol. 103, No. 6, pp. 2229-2237. Prepublished online as a Blood First Edition Paper on November 20, 2003; DOI 10.1182/blood-2003-04-1356. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-04-1356v1 103/6/2229    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 Andreakos, E. Articles by Foxwell, B. M. Search for Related Content PubMed PubMed Citation Articles by Andreakos, E. Articles by Foxwell, B. M. Related Collections Signal Transduction Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Distinct pathways of LPS-induced NF-B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of MyD88 and Mal/TIRAP Evangelos Andreakos, Sandra M. Sacre, Clive Smith, Anna Lundberg, Serafim Kiriakidis, Tim Stonehouse, Claudia Monaco, Marc Feldmann, and Brian M. Foxwell From the Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom. How lipopolysaccharide (LPS) signals through toll-like receptors (TLRs) to induce nuclear factor (NF)–B and inflammatory cytokines in sepsis remains unclear. Major candidates for that process are myeloid differentiation protein 88 (MyD88) and MyD88 adaptor-like/TIR domain-containing adaptor protein (Mal/TIRAP) but their role needs to be further defined. Here, we have examined the role of MyD88 and Mal/TIRAP in primary human cells of nonmyeloid and myeloid origin as physiologically relevant systems. We found that MyD88 and Mal/TIRAP are essential for LPS-induced IB phosphorylation, NF-B activation, and interleukin 6 (IL-6) or IL-8 production in fibroblasts and endothelial cells in a pathway that also requires IKK2. In contrast, in macrophages neither MyD88, Mal/TIRAP, nor IB kinase 2 (IKK2) are required for NF-B activation or tumor necrosis factor (TNF), IL-6, or IL-8 production, although Mal/TIRAP is still involved in the production of interferon (IFN). Differential usage of TLRs may account for that, as in macrophages but not fibroblasts or endothelial cells, TLR4 is expressed in high levels at the cell surface, and neutralization of TLR4 but not TLR2 blocks LPS signaling. These observations demonstrate for the first time the existence of 2 distinct pathways of LPS-induced NF-B activation and cytokine production in human myeloid and nonmyeloid cells defined by selective utilization of TLR4, MyD88, Mal/TIRAP, and IKK2, and reveal a layer of complexity not previously expected. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. L. Lloyd-Jones, M. M. Kelly, and P. Kubes Varying Importance of Soluble and Membrane CD14 in Endothelial Detection of Lipopolysaccharide J. Immunol., July 15, 2008; 181(2): 1446 - 1453. [Abstract] [Full Text] [PDF] P. Gong, D. J. Angelini, S. Yang, G. Xia, A. S. Cross, D. Mann, D. D. Bannerman, S. N. Vogel, and S. E. Goldblum TLR4 Signaling Is Coupled to SRC Family Kinase Activation, Tyrosine Phosphorylation of Zonula Adherens Proteins, and Opening of the Paracellular Pathway in Human Lung Microvascular Endothelia J. Biol. Chem., May 9, 2008; 283(19): 13437 - 13449. [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] A. R. Anand, M. Cucchiarini, E. F. Terwilliger, and R. K. Ganju The Tyrosine Kinase Pyk2 Mediates Lipopolysaccharide-Induced IL-8 Expression in Human Endothelial Cells J. Immunol., April 15, 2008; 180(8): 5636 - 5644. [Abstract] [Full Text] [PDF] N. Semaan, G. Alsaleh, J.-E. Gottenberg, D. Wachsmann, and J. Sibilia Etk/BMX, a Btk Family Tyrosine Kinase, and Mal Contribute to the Cross-Talk between MyD88 and FAK Pathways J. Immunol., March 1, 2008; 180(5): 3485 - 3491. [Abstract] [Full Text] [PDF] Y. Sawa, T. Ueki, M. Hata, K. Iwasawa, E. Tsuruga, H. Kojima, H. Ishikawa, and S. Yoshida LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 Expression in Human Lymphatic Endothelium J. Histochem. Cytochem., February 1, 2008; 56(2): 97 - 109. [Abstract] [Full Text] [PDF] A. M. Lundberg, S. K. Drexler, C. Monaco, L. M. Williams, S. M. Sacre, M. Feldmann, and B. M. Foxwell Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems Blood, November 1, 2007; 110(9): 3245 - 3252. [Abstract] [Full Text] [PDF] S. M Sacre, S. K Drexler, E. Andreakos, M. Feldmann, F. M Brennan, and B. M J Foxwell Could toll-like receptors provide a missing link in chronic inflammation in rheumatoid arthritis? Lessons from a study on human rheumatoid tissue Ann Rheum Dis, November 1, 2007; 66(suppl_3): iii81 - iii86. [Abstract] [Full Text] [PDF] N. Tamassia, V. Le Moigne, F. Calzetti, M. Donini, S. Gasperini, T. Ear, A. Cloutier, F. O. Martinez, M. Fabbri, M. Locati, et al. The MYD88-Independent Pathway Is Not Mobilized in Human Neutrophils Stimulated via TLR4 J. Immunol., June 1, 2007; 178(11): 7344 - 7356. [Abstract] [Full Text] [PDF] M. Sanchez-Alavez and T. Bartfai It all happens between Toll receptors and Caspase 1 PNAS, May 8, 2007; 104(19): 7733 - 7734. [Full Text] [PDF] A. V. Tsytsykova, J. V. Falvo, M. Schmidt-Supprian, G. Courtois, D. Thanos, and A. E. Goldfeld Post-induction, Stimulus-specific Regulation of Tumor Necrosis Factor mRNA Expression J. Biol. Chem., April 20, 2007; 282(16): 11629 - 11638. [Abstract] [Full Text] [PDF] S. M. Sacre, A. M. C. Lundberg, E. Andreakos, C. Taylor, M. Feldmann, and B. M. Foxwell Selective Use of TRAM in Lipopolysaccharide (LPS) and Lipoteichoic Acid (LTA) Induced NF-{kappa}B Activation and Cytokine Production in Primary Human Cells: TRAM Is an Adaptor for LPS and LTA Signaling J. Immunol., February 15, 2007; 178(4): 2148 - 2154. [Abstract] [Full Text] [PDF] S. M. Sacre, E. Andreakos, S. Kiriakidis, P. Amjadi, A. Lundberg, G. Giddins, M. Feldmann, F. Brennan, and B. M. Foxwell The Toll-Like Receptor Adaptor Proteins MyD88 and Mal/TIRAP Contribute to the Inflammatory and Destructive Processes in a Human Model of Rheumatoid Arthritis Am. J. Pathol., February 1, 2007; 170(2): 518 - 525. [Abstract] [Full Text] [PDF] M. B. Fessler, P. G. Arndt, I. Just, J. A. Nick, K. C. Malcolm, and G. Scott Worthen Dual role for RhoA in suppression and induction of cytokines in the human neutrophil Blood, February 1, 2007; 109(3): 1248 - 1256. [Abstract] [Full Text] [PDF] D. J. Davidson, A. J. Currie, D. M. E. Bowdish, K. L. Brown, C. M. Rosenberger, R. C. Ma, J. Bylund, P. A. Campsall, A. Puel, C. Picard, et al. IRAK-4 Mutation (Q293X): Rapid Detection and Characterization of Defective Post-Transcriptional TLR/IL-1R Responses in Human Myeloid and Non-Myeloid Cells J. Immunol., December 1, 2006; 177(11): 8202 - 8211. [Abstract] [Full Text] [PDF] E. Andreakos, R. O. Williams, J. Wales, B. M. Foxwell, and M. Feldmann Activation of NF-{kappa}B by the intracellular expression of NF-{kappa}B-inducing kinase acts as a powerful vaccine adjuvant PNAS, September 26, 2006; 103(39): 14459 - 14464. [Abstract] [Full Text] [PDF] O. A. Harari, P. Alcaide, D. Ahl, F. W. Luscinskas, and J. K. Liao Absence of TRAM Restricts Toll-Like Receptor 4 Signaling in Vascular Endothelial Cells to the MyD88 Pathway Circ. Res., May 12, 2006; 98(9): 1134 - 1140. [Abstract] [Full Text] [PDF] S. Jeyaseelan, R. Manzer, S. K. Young, M. Yamamoto, S. Akira, R. J. Mason, and G. S. Worthen Toll-IL-1 Receptor Domain-Containing Adaptor Protein Is Critical for Early Lung Immune Responses against Escherichia coli Lipopolysaccharide and Viable Escherichia coli J. Immunol., December 1, 2005; 175(11): 7484 - 7495. [Abstract] [Full Text] [PDF] K. D. Fairchild, I. S. Singh, H. C. Carter, L. Hester, and J. D. Hasday Hypothermia enhances phosphorylation of I{kappa}B kinase and prolongs nuclear localization of NF-{kappa}B in lipopolysaccharide-activated macrophages Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1114 - C1121. [Abstract] [Full Text] [PDF] S. R. Coats, T.-T. T. Pham, B. W. Bainbridge, R. A. Reife, and R. P. Darveau MD-2 Mediates the Ability of Tetra-Acylated and Penta-Acylated Lipopolysaccharides to Antagonize Escherichia coli Lipopolysaccharide at the TLR4 Signaling Complex J. Immunol., October 1, 2005; 175(7): 4490 - 4498. [Abstract] [Full Text] [PDF] L. C. Parker, M. K. B. Whyte, S. K. Dower, and I. Sabroe The expression and roles of Toll-like receptors in the biology of the human neutrophil J. Leukoc. Biol., June 1, 2005; 77(6): 886 - 892. [Abstract] [Full Text] [PDF] R. Jimenez, E. Belcher, S. Sriskandan, R. Lucas, S. McMaster, I. Vojnovic, T. D. Warner, and J. A. Mitchell Role of Toll-like receptors 2 and 4 in the induction of cyclooxygenase-2 in vascular smooth muscle PNAS, March 22, 2005; 102(12): 4637 - 4642. [Abstract] [Full Text] [PDF] T. Syrovets, B. Buchele, C. Krauss, Y. Laumonnier, and T. Simmet Acetyl-Boswellic Acids Inhibit Lipopolysaccharide-Mediated TNF-{alpha} Induction in Monocytes by Direct Interaction with I{kappa}B Kinases J. Immunol., January 1, 2005; 174(1): 498 - 506. [Abstract] [Full Text] [PDF] S. M. Sacre, E. Andreakos, M. Feldmann, and B. M. Foxwell Endotoxin signaling in human macrophages: signaling via an alternate mechanism Innate Immunity, December 1, 2004; 10(6): 445 - 452. [Abstract] [PDF]

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020