title: Low-dose endotoxin induces inflammation by selectively removing nuclear receptors and activating CCAAT/enhancer-binding protein δ.
abstract: Subclinical levels of circulating endotoxin are associated with the pathogenesis of diverse human inflammatory diseases, by mildly inducing the expression of proinflammatory mediators. In this study, we examined the molecular mechanism responsible for the effect of low-dose LPS in macrophages. In contrast to high-dose LPS, which activates NF-κB and induces the robust expression of proinflammatory mediators, we observed that low-dose LPS failed to activate NF-κB. Instead, it selectively activated C/EBPδ and removed nuclear repressors, including peroxisome proliferator-activated receptor α and retinoic acid receptor α, enabling a mild and leaky expression of proinflammatory mediators. The effect of low-dose LPS required IRAK-1, which interacts with and acts upstream of IκB kinase ε to contribute to LPS-mediated induction of C/EBPδ and proinflammatory mediators. Additionally, mice fed a high-fat diet acquired elevated levels of endotoxin and proinflammatory mediators in an IRAK-1-dependent fashion. Taken together, these data reveal a distinct pathway preferentially used by low-dose endotoxin in initiating low-grade inflammation.
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Urmila
authors.initials: U
authors.lastname: Maitra
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Samantha
authors.initials: S
authors.lastname: Chang
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D004731:Endotoxins / Q000502:physiology / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism / Q000502:physiology; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000502:physiology* / Q000633:toxicity; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D004731:Endotoxins; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; C491366:Nfkbie protein, mouse; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse