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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 Immunobiology Signal Transduction 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: Y.-C. Lu, I. Kim, E. Lye, F. Shen, N. Suzuki, S. Suzuki, S. Gerondakis, S. Akira, S. L. Gaffen, W.-C. Yeh, et al. Differential Role for c-Rel and C/EBP{beta}/{delta} in TLR-Mediated Induction of Proinflammatory Cytokines J. Immunol., June 1, 2009; 182(11): 7212 - 7221. [Abstract] [Full Text] [PDF] K. L. Lloyd-Jones, M. M. 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