title: Endotoxin signaling in human macrophages: signaling via an alternate mechanism.
abstract: 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.
authors.affiliation: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sacre
authors.forename: Evangelos
authors.initials: E
authors.lastname: Andreakos
authors.forename: Mark
authors.initials: M
authors.lastname: Feldmann
authors.forename: Brian M
authors.initials: BM
authors.lastname: Foxwell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D051550:I-kappa B Kinase; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity; D013583:Synovial Membrane / Q000166:cytology; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C499045:TIRAP protein, mouse; D051193:Toll-Like Receptors; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse