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Lipopolysaccharide (LPS) signals through Toll-like receptors (TLRs) in the course of sepsis, resulting in the release of inflammatory factors. In cell lines and murine models, parts of the signaling pathways involved have been elucidated with MyD88, Mal/TIRAP and IKK2 playing an important role in the induction of NF-kappaB. By focusing on primary human cells, we have shown that there are fundamental signaling differences between human and murine macrophages and between cells of myeloid and non-myeloid origins. In primary human cells, there are no available knockouts so we employed the use of dominant negatives to investigate the signaling cascades. We show that in primary human macrophages MyD88, Mal/TIRAP and IKK2-independent alternative pathways activate NF-kappaB and induce the expression of inflammatory cytokines, whereas in non-myeloid synovial fibroblasts MyD88 and/or Mal/TIRAP are essential adaptors for LPS signaling.

Original publication

DOI

10.1179/096805104225005878

Type

Journal article

Journal

Journal of endotoxin research

Publication Date

01/2004

Volume

10

Pages

445 - 452

Addresses

Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.

Keywords

Synovial Membrane, Cells, Cultured, Fibroblasts, Macrophages, Animals, Humans, Mice, Adenoviridae, Protein-Serine-Threonine Kinases, Lipopolysaccharides, Adaptor Proteins, Signal Transducing, NF-kappa B, Membrane Glycoproteins, Receptors, Cell Surface, Receptors, Immunologic, Receptors, Interleukin-1, Antigens, Differentiation, Flow Cytometry, Signal Transduction, Species Specificity, Dose-Response Relationship, Drug, Toll-Like Receptors, I-kappa B Kinase, Myeloid Differentiation Factor 88