Cited by 1,442Immune Response and InflammationSepsis Diagnosis and TreatmentInflammation biomarkers and pathways

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Receptor-Dependent Mechanisms of Cell Stimulation by Bacterial Endotoxin

Ulevitch, R J, Tobias, P S·1995·Annual Review of Immunology

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Abstract

In humans and experimental animals the presence of bacterial lipopolysaccharide (endotoxin, LPS) signals the presence of gram-negative bacteria. Recognition of LPS triggers gene induction by myeloid and nonmyeloid lineage cells. These inducible genes encode proteins that include cytokines, adhesive proteins, and enzymes that produce low molecular weight proinflammatory mediators. Together the products of these inducible genes upregulate host defense systems that participate in eliminating the bacterial infection. Unfortunately, these same mediators contribute to a serious human disease known as septic shock. Considerable progress has been made during the past decade in determining the sources, identities, and sequence of release of these mediators. In contrast, until recently, marked gaps in our knowledge existed regarding the identity of the LPS receptor and intracellular signaling pathways responsible for LPS-induced cell activation. The discovery in 1986 of a plasma protein termed LPS binding protein (LBP) led to the discovery of unanticipated mechanisms of LPS-induced cell activation. CD14 was found as a soluble serum protein or as a glycosylphosphatidylinositol (GPI)-anchored protein of myeloid lineage cells; it now occupies a key role in LPS-induced cell activation as we understand it today. Here we discuss how LBP enables LPS binding to CD14 and how complexes of LPS and soluble or GPI-anchored CD14 participate in cell activation. We also review the evidence supporting a model for a functional LPS receptor of myeloid cells, which is multimeric, comprised of GPI-anchored CD14 and a presently unidentified transmembrane protein that together bind LPS and initiate cell activation via kinase cascades.

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Heat Shock Response Inhibits NF-κB Activation and Cytokine Production in Murine Kupffer Cells
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“Bacterial lipopolysaccharide (LPS), a cell wall constituent of Gram-negative bacteria, is a potent activator of mammalian cells such as macrophages [1].”
Background
Syntheses of Prostaglandin E2 and E-Cadherin and Gene Expression of β-defensin-2 by Human Gingival Epithelial Cells in Response to Actinobacillus actinomycetemcomitans
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“hBD-1 is constitutively expressed in the respiratory tract, kidney, and urogenital epithelium and is not regulated by inflammatory or bacterial stimuli (7, 40, 41).”
Background
Effect of an acidic heteropolysaccharide (ARAGAL) from the gum of Anadenanthera colubrina (Angico branco) on peritoneal macrophage functions
Moretão, M. P., Buchi, D. F., Gorin, P. A. J., Iacomini, M., & de Oliveira, M. B. M. (2003) · Immunology Letters · doi:10.1016/s0165-2478(03)00136-6 · Cited by 54
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Role of Toll-like receptor 4 on pancreatic and pulmonary injury in a mice model of acute pancreatitis associated with endotoxemia
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“LPS is long known to act through the membranebound CD14 receptor in monocytes and macrophages (18, 19).”
Background
The p38 MAPK Pathway Mediates Transcriptional Activation of the Plasma Platelet-activating Factor Acetylhydrolase Gene in Macrophages Stimulated with Lipopolysaccharide
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Toll‐like Receptor Signaling and Chemokine Receptor Expression Influence the Severity of Urinary Tract Infection
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“LPS binding protein transfers LPS to a binding site on CD14, and cell activation occurs through the recruitment of Toll-like receptors (TLRs) [13, 14].”
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CdTe quantum dots as a novel biosensor for Serratia marcescens and Lipopolysaccharide
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“CD14, the receptor for LPS, is implicated in various immune responses including activation of the innate immune system (6), bacterial phagocytosis (7), and clearance of apoptotic cells (8).”
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Pellino3 Is a Novel Upstream Regulator of p38 MAPK and Activates CREB in a p38-dependent Manner
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Protein C Replacement in Severe Meningococcemia: Rationale and Clinical Experience
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“The end results of lipopolysaccharide action are complement activation generating the membrane attack complex C5b9 [13, 14] and synthesis of inﬂammatory mediators, including platelet-activating factor and an array of proinﬂammatory cytokines [15].”
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Endotoxin Activation of Macrophages Does Not Induce ATP Release and Autocrine Stimulation of P2 Nucleotide Receptors
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“Endotoxin-induced signaling is serum dependent due to a requirement for LPS-binding protein (2).”
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The Lps locus: Genetic regulation of host responses to bacterial lipopolysaccharide
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Background
Functional roles of SPLUNC1 in the innate immune response against Gram-negative bacteria
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“The average molecular weight of 1 × 106 of 𝜅- carrageenan was used in this experiment.”
Method
Genes, Receptors, Signals and Responses to Lipopolysaccharide Endotoxin
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Stimulant-Dependent Modulation of Cytokines and Chemokines by Airway Epithelial Cells: Cross Talk between Pulmonary Epithelial and Peripheral Blood Mononuclear Cells
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“cytes/macrophages and other cells (10, 32).”
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Adenovirus infection induces microglial activation: involvement of mitogen-activated protein kinase pathways
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Role of Macrophage Migration Inhibitory Factor in Acute Lung Injury in Mice with Acute Pancreatitis Complicated by Endotoxemia
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“LPS stimulates cells by interaction with CD-14 in the context of TLR (38).”
Background
Amygdalar activation alters the hippocampal GABA system: ?Partial? modelling for postmortem changes in schizophrenia
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Differential Regulation of Lipopolysaccharide (LPS) Activation Pathways in Mouse Macrophages by LPS-Binding Proteins
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STAT1 Regulates Lipopolysaccharide- and TNF-α-Dependent Expression of Transporter Associated with Antigen Processing 1 and Low Molecular Mass Polypeptide 2 Genes in Macrophages by Distinct Mechanisms
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“LPS, a component of bacterial cell walls, is a potent macrophage-activating stimulus, which induces the expression of many genes necessary for host defense function (24).”
Background
Preprosomatostatin Messenger RNA Is Expressed by Inflammatory Cells and Induced by Inflammatory Mediators and Cytokines
Elliott, D. E., Blum, A. M., Li, J., Metwali, A., & Weinstock, J. V. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.8.3997 · Cited by 51
Aerosolized endotoxin is immediately bound by pulmonary surfactant protein D in vivo
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Lipopolysaccharide induces functional ICAM-1 expression in rat alveolar epithelial cells in vitro
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“Evidence has grown that a soluble form of CD14, a macrophage and granulocyte membrane protein, forms complexes, with LPS binding to specific signal-transducing receptors on epithelial or endothelial cells (13, 26, 37).”
Background
Probiotic genomic DNA reduces the production of pro-inflammatory cytokine tumor necrosis factor-alpha
Kim, C. H., Kim, H. G., Kim, J. Y., Kim, N. R., Jung, B. J., Jeong, J. H., & Chung, D. K. (2011) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.2011.02470.x · Cited by 50
“Recent reports have explained a general pathway involving the interaction between LPS and TLR (Ulevitch & Tobias, 1995; Lakhani & Bogue, 2003).”
Background
Lesional Accumulation of CD163-Expressing Cells in the Gut of Patients with Inflammatory Bowel Disease
Franzè, E., Caruso, R., Stolfi, C., Sarra, M., Cupi, M. L., Caprioli, F., Monteleone, I., Zorzi, F., Nitto, D. D., Colantoni, A., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069839 · Cited by 50
“(interleukin)-10, IL-25] and are able to engulf and kill microbes without eliciting inflammatory responses [3,4,5].”
Anti-CD14 antibody reduces LPS responsiveness via TLR4 internalization in human monocytes
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Particulate matter exposure is associated with inflammatory gene methylation in obese subjects
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“, 2015) and it performs as a component of the innate immune system (Ulevitch and Tobias, 1995).”
Background
Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells
Lee, J. H., Park, E., Kim, O. S., Kim, H. Y., Joe, E.-H., & Jou, I. (2005) · Glia · doi:10.1002/glia.20156 · Cited by 52
LPS-induced cytokine production and expression of LPS-receptors by peripheral blood mononuclear cells of patients with familial hypercholesterolemia and the effect of HMG-CoA reductase inhibitors
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Authors: Ulevitch, R. J., & Tobias, P. S.
Affiliations: Scripps Research Institute (US)
ORCID: Ulevitch, R J
Venue: Annual Review of Immunology
Publisher: Annual Reviews
Published: 1995-04
Volume: 13
Issue: 1
Pages: 437-457
ISSN: 0732-0582 (ISSN-L)
1545-3278
DOI: 10.1146/annurev.iy.13.040195.002253
OpenAlex: W2113828544
Cited by: 1,442
References: 36
Citations by year: 2026: 4 · 2025: 11 · 2024: 8 · 2023: 11 · 2022: 13 · 2021: 25 · 2020: 23 · 2019: 21 · 2018: 22 · 2017: 24 · 2016: 37 · 2015: 29 · 2014: 39 · 2013: 43 · 2012: 38
FWCI: 20.96
Type: journal article
Language: en
Open access: closed
Locations: Annual Review of Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of General Medical Sciences (GM28485, GM3769)
National Institute of Allergy and Infectious Diseases (AI 15136, R01AI015136)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords: lipopolysaccharide, endotoxin, LPS receptor, CD14, LPS-binding protein, septic shock, myeloid cells, intracellular signaling, transmembrane proteins, pro-inflammatory mediators
MeSH terms: Lipopolysaccharide-Binding Protein, Acute-Phase Proteins, Amino Acid Sequence, Animals, Carbohydrate Sequence, Carrier Proteins, Humans, Lipopolysaccharides, Membrane Glycoproteins, Models, Biological, Molecular Sequence Data, Receptors, Immunologic, Shock, Septic, Antigens, Differentiation, Myelomonocytic, Molecular Structure, Signal Transduction, Antigens, CD, Calcium-Calmodulin-Dependent Protein Kinases, Lipopolysaccharide Receptors

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Receptor-Dependent Mechanisms of Cell Stimulation by Bacterial Endotoxin

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