Molecular mechanisms responsible for the selective and low-grade induction of proinflammatory mediators in murine macrophages by lipopolysaccharide.
Low-dose endotoxemia is prevalent in humans with adverse health conditions, and it correlates with the pathogenesis of chronic inflammatory diseases such as atherosclerosis, diabetes, and neurologic inflammation. However, the underlying molecular mechanisms are poorly understood. In this study, we demonstrate that subclinical low-dose LPS skews macrophages into a mild proinflammatory state, through cell surface TLR4, IL-1R-associated kinase-1, and the Toll-interacting protein. Unlike high-dose LPS, low-dose LPS does not induce robust activation of NF-κB, MAPKs, PI3K, or anti-inflammatory mediators. Instead, low-dose LPS induces activating transcription factor 2 through Toll-interacting protein-mediated generation of mitochondrial reactive oxygen species, allowing mild induction of proinflammatory mediators. Low-dose LPS also suppresses PI3K and related negative regulators of inflammatory genes. Our data reveal novel mechanisms responsible for skewed and persistent low-grade inflammation, a cardinal feature of chronic inflammatory diseases.
Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
Urmila
U
Maitra
Hui
H
Deng
Trevor
T
Glaros
Bianca
B
Baker
Daniel G S
DG
Capelluto
Zihai
Z
Li
Liwu
L
Li
D051698:Activating Transcription Factor 2 / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005786:Gene Expression Regulation / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000502:physiology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000276:immunology / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; C485837:Tollip protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D053592:Interleukin-1 Receptor-Associated Kinases