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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Background
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Background
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Background
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Background
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“membrane receptor (4, 5) as well as toll-like receptors,”
Background
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“LPS was also included as positive control [41].”
Background
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“LPS, an amphiphilic molecule in the outer membrane of Gram-negative bacteria, is involved in bone resorption in inflammatory diseases (10).”
Background
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“CD14 is either membrane-bound with a glycosylphosphatidylinositol anchor or present as a soluble molecule (soluble CD14 [sCD14]) after secretion or enzymatically cleavage (10).”
Background
Increased Levels of Soluble CD14 in Sera of Periodontitis Patients
Hayashi, J., Masaka, T., & Ishikawa, I. (1999) · Infection and Immunity · doi:10.1128/iai.67.1.417-420.1999 · Cited by 75
Similar Organization of the Lipopolysaccharide-Binding Protein (LBP) and Phospholipid Transfer Protein (PLTP) Genes Suggests a Common Gene Family of Lipid-Binding Proteins
Kirschning, C. J., Au-Young, J. K., Lamping, N., Reuter, D., Pfeil, D., Seilhamer, J. J., & Schumann, R. R. (1997) · Genomics · doi:10.1006/geno.1997.5030 · Cited by 73
Molecular Mechanisms of Innate Immunity
Ulevitch, R. J. (2000) · Immunologic Research · doi:10.1385/ir:21:2-3:49 · Cited by 73
Self-citation
Heparin-Binding Protein (CAP37) Is Internalized in Monocytes and Increases LPS-Induced Monocyte Activation
Heinzelmann, M., Mercer-Jones, M. A., Flodgaard, H. J., & Miller, F. N. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.11.5530 · Cited by 73
A Phase 2 Randomized, Double-Blind, Placebo–Controlled Study of the Safety and Efficacy of Talactoferrin in Patients With Severe Sepsis*
Guntupalli, K. K., Dean, N. C., Morris, P. E., Bandi, V., Margolis, B. D., Rivers, E., Levy, M. M., Lodato, R. F., Ismail, P. M., Reese, A., et al. (2013) · Critical Care Medicine · doi:10.1097/ccm.0b013e3182741551 · Cited by 72
Aggregation Behavior of an Ultra-Pure Lipopolysaccharide that Stimulates TLR-4 Receptors
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“This raises the possibility that the critical aggregation concentration in culture medium could be different due to the binding of LPS to serum components such as LBP, sCD14, and lipoproteins (5,41).”
Background
Complement-Dependent Accumulation and Degradation of Platelets in the Lung and Liver Induced by Injection of Lipopolysaccharides
Shibazaki, M., Kawabata, Y., Yokochi, T., Nishida, A., Takada, H., & Endo, Y. (1999) · Infection and Immunity · doi:10.1128/iai.67.10.5186-5191.1999 · Cited by 72
Role of NF-kB and p38 MAP Kinase Signaling Pathways in the Lipopolysaccharide-Dependent Activation of Heme Oxygenase-1 Gene Expression
Wijayanti, N., Huber, S., Samoylenko, A., Kietzmann, T., & Immenschuh, S. (2004) · Antioxidants and Redox Signaling · doi:10.1089/ars.2004.6.802 · Cited by 71
Antiendotoxin Strategies for the Prevention and Treatment of Septic Shock
Opal, S. M., & Yu, R. L. (1998) · Drugs · doi:10.2165/00003495-199855040-00002 · Cited by 71
Understanding the mechanism of action of bacterial superantigens from a decade of research
Lavoie, P. M., Thibodeau, J., Erard, F., & Sékaly, R. (1999) · Immunological Reviews · doi:10.1111/j.1600-065x.1999.tb01297.x · Cited by 71
The wild-derived inbred mouse strain SPRET/Ei is resistant to LPS and defective in IFN-β production
Mahieu, T., Park, J. M., Revets, H., Pasche, B., Lengeling, A., Staelens, J., Wullaert, A., Vanlaere, I., Hochepied, T., van Roy, F., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510874103 · Cited by 70
Dendritic Cell Activation and Cytokine Production Induced by Group BNeisseria meningitidis: Interleukin-12 Production Depends on Lipopolysaccharide Expression in Intact Bacteria
Dixon, G. L. J., Newton, P., Chain, B., Katz, D. R., Andersen, S. R., Wong, S. Y. C., van der Ley, P., Klein, N. J., & Callard, R. E. (2001) · Infection and Immunity · doi:10.1128/iai.69.7.4351-4357.2001 · Cited by 70
“host inflammatory responses (40) and was considered to be the”
Background
Endotoxin opens the Toll gates to innate immunity
Ulevitch, R. J. (1999) · Nature Medicine · doi:10.1038/5504 · Cited by 70
Self-citation
Lipopolysaccharide tolerance in murine peritoneal macrophages induces downregulation of the lipopolysaccharide signal transduction pathway through mitogen-activated protein kinase and nuclear factor-κB cascades, but not lipopolysaccharide-incorporation steps
Tominaga, K., Saito, S., Matsuura, M., & Nakano, M. (1999) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(99)00037-3 · Cited by 70
Mannan-binding lectin regulates dendritic cell maturation and cytokine production induced by lipopolysaccharide
Wang, M., Zhang, Y., Chen, Y., Zhang, L., Lu, X., & Chen, Z. (2011) · BMC Immunology · doi:10.1186/1471-2172-12-1 · Cited by 69
“LPS-activated cells sometimes induce microcirculatory dysfunction as well as inflammatory changes, which cause injury to various tissues, circulatory failure, and occasionally death [36-38].”
Background
Toll gates for pathogen selection
Ulevitch, R. J. (1999) · Nature · doi:10.1038/44490 · Cited by 69
Self-citation
Toll-like receptor signalling and the clinical benefits that lie within
Verstak, B., Hertzog, P. J., & Mansell, A. S. (2007) · Inflammation Research · doi:10.1007/s00011-007-6093-7 · Cited by 69
CD14-independent activation of cardiomyocyte signal transduction by bacterial endotoxin
Cowan, D. B., Poutias, D., del Nido, P. J., & McGowan, F. X. J. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.279.2.h619 · Cited by 69
“, endothelial, epithelial, and smooth muscle cells) (31, 40, 54).”
BackgroundInfluential
Genetic Control of Experimental Lyme Arthritis in the Absence of Specific Immunity
Brown, C. R., & Reiner, S. L. (1999) · Infection and Immunity · doi:10.1128/.67.4.1967-1973.1999 · Cited by 67
Role of lipopolysaccharide susceptibility in the innate immune response to infection: LPS, a primary target for recognition of Gram-negative bacteria
Freudenberg, M. A., Merlin, T., Gumenscheimer, M., Kalis, C., Landmann, R. M., & Galanos, C. (2001) · Microbes and Infection · doi:10.1016/s1286-4579(01)01481-2 · Cited by 68
Fas/Fas Ligand System Mediates Epithelial Injury, but Not Pulmonary Host Defenses, in Response to Inhaled Bacteria
Matute‐Bello, G., Frevert, C. W., Liles, W. C., Nakamura, M., RUZINSKI, J. T., Ballman, K. K., Wong, V. A., Vathanaprida, C., & Martin, T. R. (2001) · Infection and Immunity · doi:10.1128/iai.69.9.5768-5776.2001 · Cited by 68
“For example, E. coli infection can result in PMN recruitment thru activation of CD14dependent pathways, with the generation of endogenous chemoattractants, such as IL-8 (4, 28).”
BackgroundInfluential
Association of the −159 CD14 gene polymorphism and lack of association of the −308 TNFA and Q551R IL‐4RA polymorphisms with severe chronic periodontitis in Swedish Caucasians
Donati, M., Berglundh, T., Hytönen, A.-M., Hahn‐Zoric, M., Hanson, L., & Padyukov, L. (2005) · Journal Of Clinical Periodontology · doi:10.1111/j.1600-051x.2005.00697.x · Cited by 68
Differential Deactivation of Human Dendritic Cells by Endotoxin Desensitization: Role of Tumor Necrosis Factor-α and Prostaglandin E2
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Structural Regions of MD-2 That Determine the Agonist-Antagonist Activity of Lipid IVa
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Increased adipose tissue secretion of Fetuin-A, lipopolysaccharide-binding protein and high-mobility group box protein 1 in metabolic syndrome
Jialal, I., Devaraj, S., Bettaieb, A., Haj, F. G., & ADAMS-HUET, B. A. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.04.814 · Cited by 67
Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses.
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Differential Effects of Lipopolysaccharide and Tumor Necrosis Factor on Monocytic IκB Kinase Signalsome Activation and IκB Proteolysis
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Tissue Injury and Cellular Immune Responses to Cadmium Chloride Exposure in the Common Mussel Mytilus edulis: Modulation by Lipopolysaccharide
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“Lipopolysaccharides (LPSs) are found on the external membranes of Gram-negative bacteria and are known to stimulate immune responses in eukaryote organisms by several methods, including the activation of signal transduction pathways in macrophages (Ulevitch and Tobias 1995).”
Background
Proteoglycan Isolated from Phellinus linteus Induces Toll-Like Receptors 2- and 4-Mediated Maturation of Murine Dendritic Cells via Activation of ERK, p38, and NF-.KAPPA.B
Kim, G., Han, M.-G., Song, Y., Shin, B., Shin, Y., Lee, H.-J., Moon, D., Lee, C.-M., Kwak, J., Bae, Y., et al. (2004) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.27.1656 · Cited by 66
Morphologic, physiological and immunological changes of haemocytes from Litopenaeus vannamei treated by lipopolysaccharide
Xian, J.-A., Wang, A., Tian, J., Huang, J., Ye, C., Wang, W., & Sun, R. (2009) · Aquaculture · doi:10.1016/j.aquaculture.2009.10.008 · Cited by 67
Osteoclast activation in inflammatory periodontal diseases
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Roles of neuronal toll-like receptors in neuropathic pain and central nervous system injuries and diseases
Acıoğlu, Ç., Heary, R. F., & Elkabes, S. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.02.016 · Cited by 67
“For example, several receptor complexes have been described for TLR4 (Miyake, 2004; Shimazu et al., 1999; Ulevitch and Tobias, 1995).”
Ganoderic acid C1 isolated from the anti-asthma formula, ASHMI™ suppresses TNF-α production by mouse macrophages and peripheral blood mononuclear cells from asthma patients
Liu, C., Yang, N., Song, Y., Wang, L., Zi, J., Zhang, S., Dunkin, D., Busse, P. J., Weir, D., Tversky, J. R., et al. (2015) · International Immunopharmacology · doi:10.1016/j.intimp.2015.05.018 · Cited by 65
“Increased levels of phosphorylated- IκB-α (p-IκBα) protein and p65 in cytosol and nuclear p-p65 indicate heightened NF-κB activation (Ulevitch and Tobias, 1995).”
Background
Epigenetic Modification of TLRs in Leukocytes Is Associated with Increased Susceptibility to Salmonella enteritidis in Chickens
Gou, Z., Liu, R., Zhao, G., Zheng, M., Li, P., Wang, H., Zhu, Y., Chen, J., & Wen, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033627 · Cited by 65
“[6,7,8].”
Anti-inflammatory and heme oxygenase-1 inducing activities of lanostane triterpenes isolated from mushroom Ganoderma lucidum in RAW264.7 cells
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THE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME RELATED TO THE RELEASE OF CYTOKINES FOLLOWING SEVERE ENVENOMATION
Voronov, E., Apte, R. N., & Sofer, S. (1999) · Journal of Venomous Animals and Toxins · doi:10.1590/s0104-79301999000100002 · Cited by 65
Caspase-7 deficiency protects from endotoxin-induced lymphocyte apoptosis and improves survival
Lamkanfi, M., Moreira, L. O., Makena, P. S., Spierings, D. C. J., Boyd, K. L., Murray, P. J., Green, D. R., & Kanneganti, T. (2009) · Blood · doi:10.1182/blood-2008-09-178038 · Cited by 65
“These cytokines and chemokines are believed to be important mediators of organ injury in endotoxic shock.(20,21,23) Therefore, we addressed whether caspase-7 mediates lymphocyte apoptosis indirectly by”
Immortalization of Human Urethral Epithelial Cells: a Model for the Study of the Pathogenesis of and the Inflammatory Cytokine Response to Neisseria gonorrhoeae Infection
Harvey, H. A., Post, D. M. B., & Apicella, M. A. (2002) · Infection and Immunity · doi:10.1128/iai.70.10.5808-5815.2002 · Cited by 66
“Similar to other pathogenic bacterial endotoxins (4, 22, 25, 29, 30), gonococcal lipooligosaccharide (LOS) is believed to play a role in the inflammatory response (12, 24, 27).”
Background
Peptidoglycan induces interleukin‐6 expression through the TLR2 receptor, JNK, c‐Jun, and AP‐1 pathways in microglia
Lin, H., Tang, C., Chen, J.-H., Chuang, J., Huang, S.-M., Tan, T., Lai, C., & Lu, D. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22489 · Cited by 66
“These inflammatory molecules are the major cause of the various signs and symptoms that occur during bacterial infection, including fever, inflammation, and acute phase responses (Bone, 1994; Ulevitch and Tobias, 1995; Dziarski et al., 2000).”
Background
CD14 Works with Toll‐Like Receptor 2 to Contribute to Recognition and Control ofListeria monocytogenesInfection
Janot, L., Sécher, T., Torres, D., Maillet, I., Pfeilschifter, J. M., Quesniaux, V. F. J., Landmann, R. M., Ryffel, B., & Erard, F. (2008) · The Journal of Infectious Diseases · doi:10.1086/588815 · Cited by 65
“of proinflammatory cytokines [7, 8].”
New Scavenger Receptor-Like Receptors for the Binding of Lipopolysaccharide to Liver Endothelial and Kupffer Cells
van Oosten, M., van de Bilt, E., van Berkel, T. J. C., & Kuiper, J. (1998) · Infection and Immunity · doi:10.1128/iai.66.11.5107-5112.1998 · Cited by 64

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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