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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Background
B7-H1 and B7-DC receptors of oral squamous carcinoma cells are upregulated by Porphyromonas gingivalis
Groeger, S. E., Domann, E., Gonzales, J. R., Chakraborty, T., & Meyle, J. (2011) · Immunobiology · doi:10.1016/j.imbio.2011.05.005 · Cited by 134
CD14-Dependent Internalization of Bacterial Lipopolysaccharide (LPS) Is Strongly Influenced by LPS Aggregation But Not by Cellular Responses to LPS
Kitchens, R. L., & Munford, R. S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.4.1920 · Cited by 132
Mechanisms for Ovarian Cycle Disruption by Immune/inflammatory Stress
Karsch, F. J., Battaglia, D. F., Breen, K. M., Debus, N., & Harris, T. G. (2002) · Stress · doi:10.1080/10253890290027868 · Cited by 134
“…peripheral cells (monocytes, macrophages, neutrophils, fibroblasts) as well as neurons and glia, and that these cells, in turn, produce a cascade of intermediary molecules (Bradley, 1979; DeRijk et al., 1991; Schobitz et al., 1994; Ulevitch and Tobias, 1995; Van Dam et al., 1995; Rivier, 1995).”
Background
Isolation, Characterization, and Antimicrobial Properties of Bovine Oligosaccharide-binding Protein
Tydell, C. C., Yount, N. Y., Tran, D., Yuan, J. J., & Selsted, M. E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200659200 · Cited by 133
Differences in LPS‐Induced Activation of Bronchial Epithelial Cells (BEAS‐2B) and Type II‐Like Pneumocytes (A‐549)
Schulz, C. K. J., Farkas, L., WOLF, K., Krätzel, K., Eißner, G., & Pfeifer, M. A. (2002) · Scandinavian Journal of Immunology · doi:10.1046/j.1365-3083.2002.01137.x · Cited by 132
CD14 Is Expressed and Released as Soluble CD14 by Human Intestinal Epithelial Cells In Vitro: Lipopolysaccharide Activation of Epithelial Cells Revisited
Funda, D., Tučková, L., Farré, M., Iwase, T., Moro, I., & Tlaskalova-Hogenova, H. (2001) · Infection and Immunity · doi:10.1128/iai.69.6.3772-3781.2001 · Cited by 147
“mCD14 is a GPI-anchored protein; therefore, a transmembrane, signaltransducing molecule for LPS has been assumed for many years (45, 49, 50, 52).”
BackgroundInfluential
CpG-Containing Oligonucleotides Are Efficient Adjuvants for Induction of Protective Antiviral Immune Responses with T-Cell Peptide Vaccines
Oxenius, A., Martinic, M. M. A., Hengartner, H., & Klenerman, P. (1999) · Journal of Virology · doi:10.1128/jvi.73.5.4120-4126.1999 · Cited by 129
The Role of Intestinal Macrophages in Gastrointestinal Homeostasis: Heterogeneity and Implications in Disease
Yip, J. L. K., Balasuriya, G. K., Spencer, S. J., & Hill‐Yardin, E. L. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.08.021 · Cited by 130
Current Understanding of Sepsis
Wenzel, R. P., Pinsky, M. R., Ulevitch, R. J., & Young, L. D. (1996) · Clinical Infectious Diseases · doi:10.1093/clinids/22.3.407 · Cited by 130
Self-citation
Type 1 fimbriae deliver an LPS‐ and TLR4‐dependent activation signal to CD14‐negative cells
Hedlund, M., Frendéus, B., Wachtler, C., Hang, L., Fischer, H., & Svanborg, C. (2001) · Molecular Microbiology · doi:10.1046/j.1365-2958.2001.02205.x · Cited by 130
“Host cell activation through delivery of a `second signal' may be expected to involve lipopolysaccharide (LPS) as this is the principal component of Gram-negative bacteria that alerts the host to systemic infection and triggers the defence (Rietschel and Brade, 1992; Ulevitch and Tobias, 1995).”
BackgroundInfluential
Role of sulfiredoxin as a regulator of peroxiredoxin function and regulation of its expression
Jeong, W., Bae, S. H., Tolédano, M. B., & Rhee, S. G. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.05.020 · Cited by 137
“Lipopolysaccharide (LPS), an integral component of the outer membrane of gram-negative bacteria, is a potent activator of macrophages and a key mediator of endotoxic shock [67].”
Toll-like Receptor 4 Signaling Regulates Cytosolic Phospholipase A2 Activation and Lipid Generation in Lipopolysaccharide-stimulated Macrophages
Qi, H., & Shelhamer, J. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m509352200 · Cited by 130
Vibrio fischeri lipopolysaccharide induces developmental apoptosis, but not complete morphogenesis, of the Euprymna scolopes symbiotic light organ.
Foster, J. S., Apicella, M., & McFall-Ngai, M. (2000) · Developmental Biology · doi:10.1006/dbio.2000.9868 · Cited by 140
“Of the bacterial cell surface molcules implicated in eukaryotic–prokaryotic interactions, erhaps the most conspicuous and best studied is lipopolyaccharide (LPS) (Raetz et al., 1991; Raetz, 1993; Kielian and lecha, 1995; Ulevitch and Tobias, 1995; Fenton and Goenbock, 1998; Hamann et al., 1998).”
Background
Maturation of immune responses at the beginning of asthma
Martínez, F. D. (1999) · Journal of Allergy and Clinical Immunology · doi:10.1016/s0091-6749(99)70456-2 · Cited by 125
Harnessing aptamers for electrochemical detection of endotoxin
Kim, S., Su, W., Cho, M. S., Lee, Y., & Choe, W. (2012) · Analytical Biochemistry · doi:10.1016/j.ab.2012.02.016 · Cited by 127
Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells
Bai, T., Lian, L., Wu, Y., Wan, Y., & Nan, J. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2012.12.020 · Cited by 128
Lipoteichoic acids as a major virulence factor causing inflammatory responses via Toll-like receptor 2
Kang, S., Sim, J., Yun, C., & Han, S. H. (2016) · Archives of Pharmacal Research · doi:10.1007/s12272-016-0804-y · Cited by 130
Expression of multiple forms of IL-1 receptor antagonist (IL-1ra) by human retinal pigment epithelial cells: identification of a new IL-1ra exon
Holtkamp, G. M., de Vos, A. F., Kijlstra, A., & Peek, R. (1999) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199901)29:01 · Cited by 31
Supercritical carbon dioxide extract exhibits enhanced antioxidant and anti-inflammatory activities of Physalis peruviana
Wu, S.-J., Tsai, J.-Y., Chang, S.-P., Lin, D.-L., Wang, S. S., Huang, L.-J., & Ng, L. (2006) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2006.05.027 · Cited by 127
Differential expression of inducible nitric oxide synthase is associated with differential Toll-like receptor-4 expression in chicken macrophages from different genetic backgrounds
Dil, N., & Qureshi, M. A. (2002) · Veterinary Immunology and Immunopathology · doi:10.1016/s0165-2427(01)00402-0 · Cited by 126
CD14, Endotoxin, and Asthma Risk: Actions and Interactions
Martinez, F. D. (2007) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200702-035aw · Cited by 126
“From the point of view of asthma and allergies, interest in this gene was twofold: first, CD14 is located in chromosome 5q31, a region that several genome-wide searches have suggested contains variations relevant to asthma (3); and second, CD14 is a receptor that has specificity for lipopolysaccharides (LPS) and other…”
Background
Innate immunity and its role against infections
Uthaisangsook, S., Day, N. K. B., Bahna, S. L., Good, R. A., & Haraguchi, S. (2002) · Annals of Allergy Asthma & Immunology · doi:10.1016/s1081-1206(10)62005-4 · Cited by 127
Anti‐Inflammatory Effect of Quercetin on RAW 264.7 Mouse Macrophages Induced with Polyinosinic‐Polycytidylic Acid
Kim, Y., & Park, W. (2016) · Molecules · doi:10.3390/molecules21040450 · Cited by 125
Bacillus amyloliquefaciens supplementation alleviates immunological stress in lipopolysaccharide-challenged broilers at early age
Li, Y., Zhang, H., Chen, Y. P., Yang, M. X., Zhang, L. L., Lu, Z., Zhou, Y., & Wang, T. (2015) · Poultry Science · doi:10.3382/ps/pev124 · Cited by 127
“of innate immune responses that results in the production of pro- and anti-inflammatory mediators (Ulevitch and Tobias, 1995).”
Background
Innate recognition of lipopolysaccharide by CD14 and toll-like receptor 4-MD-2: unique roles for MD-2
Miyake, K. (2003) · International Immunopharmacology · doi:10.1016/s1567-5769(02)00258-8 · Cited by 126
Evaluation of the CD14 C‐159 T polymorphism in the German Multicenter Allergy Study cohort
Sengler, C., Haider, A., Sommerfeld, C., Lau, S., Baldini, M., Martínez, F. D., Wahn, U., & Nickel, R. G. (2003) · Clinical & Experimental Allergy · doi:10.1046/j.1365-2222.2003.01549.x · Cited by 125
Lipoteichoic Acids fromLactobacillus johnsoniiStrain La1 andLactobacillus acidophilusStrain La10 Antagonize the Responsiveness of Human Intestinal Epithelial HT29 Cells to Lipopolysaccharide and Gram-Negative Bacteria
Vidal, K., Donnet‐Hughes, A., & Granato, D. (2002) · Infection and Immunity · doi:10.1128/iai.70.4.2057-2064.2002 · Cited by 125
“The CD14 molecule, which is expressed primarily on monocytes and macrophages, serves as a high-affinity receptor for LPS, mediating LPS-induced cell activation (43, 46).”
Background
Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1) negatively regulates TLR4-mediated LPS response primarily through a phosphatase activity- and PI-3K-independent mechanism
An, H., Xu, H., Zhang, M., Zhou, J., Feng, T., Qian, C., Qi, R., & Cao, X. (2005) · Blood · doi:10.1182/blood-2005-01-0191 · Cited by 140
Lipoteichoic Acid Isolated from Lactobacillus plantarum Inhibits Lipopolysaccharide-Induced TNF-α Production in THP-1 Cells and Endotoxin Shock in Mice
Kim, H. G., Kim, N.-R., Gim, M. G., Lee, J. M., Lee, S. Y., Ko, M. Y., Kim, J. Y., Han, S. H., & Chung, D. K. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.4.2553 · Cited by 124
Proteolysis of monocyte CD14 by human leukocyte elastase inhibits lipopolysaccharide-mediated cell activation
Le-Barillec, K., Si‐Tahar, M., Balloy, V., & Chignard, M. (1999) · Journal of Clinical Investigation · doi:10.1172/jci5779 · Cited by 124
Pseudomonas aeruginosa lipid A diversity and its recognition by Toll-like receptor 4
Ernst, R. K., Hajjar, A. M., Tsai, J. H., Moskowitz, S. M., Wilson, C. B., & Miller, S. I. (2003) · Journal of Endotoxin Research · doi:10.1177/09680519030090060201 · Cited by 124
“This complex consists of the TLR4 receptor and two co-receptors – MD-2 (required for TLR4 function)(8,9) and CD14 (a high affinity GPI-linked LPS binding protein).(10) Interaction of lipid A with the TLR4 receptor complex triggers a phosphorylation cascade (via TRAF6 and the signaling kinases NIK and IKK) that results…”
Background
Proteolysis of Human Monocyte CD14 by Cysteine Proteinases (Gingipains) from Porphyromonas gingivalis Leading to Lipopolysaccharide Hyporesponsiveness
Sugawara, S., Nemoto, E., Tada, H., Miyake, K., Imamura, T., & Takada, H. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.1.411 · Cited by 122
“CD14, mainly expressed on monocytes, functions as a major receptor for LPS (15, 16).”
Background
Lipopolysaccharide (LPS)-binding Proteins BPI and LBP Form Different Types of Complexes with LPS
Tobias, P. S., Soldau, K., Iovine, N. M., Elsbach, P., & Weiss, J. P. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.30.18682 · Cited by 122
Self-citation
Activation of Human Leukocytes Reduces Surface P-Selectin Glycoprotein Ligand-1 (PSGL-1, CD162) and Adhesion to P-Selectin In Vitro
Davenpeck, K. L., Brummet, M. E., Hudson, S. A., Mayer, R. J., & Bochner, B. S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.5.2764 · Cited by 121
“In these experiments, monocytes were identified by their scatter characteristics and were distinguished from lymphocytes by light scatter and CD14 staining (20, 21).”
Method
Toll-like receptor 4-mediated signal pathway induced by Porphyromonas gingivalis lipopolysaccharide in human gingival fibroblasts.
Wang, P.-L., Azuma, Y., Shinohara, M., & Ohura, K. (2000) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1006/bbrc.2000.3060 · Cited by 125
Antisense oligonucleotides targeting protein kinase C-alpha, -beta I, or -delta but not -eta inhibit lipopolysaccharide-induced nitric oxide synthase expression in RAW 264.7 macrophages: involvement of a nuclear factor kappa B-dependent mechanism.
Chen, C., Wang, J. K. T., & Lin, S. (1998) · PubMed · Cited by 121
Purification and Mass Spectrometry of Six Lipid A Species from the Bacterial Endosymbiont Rhizobium etli
Que, N. L. S., Lin, S., Cotter, R. J., & Raetz, C. R. H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004008200 · Cited by 120
HSP70 gene expression in Mytilus galloprovincialis hemocytes is triggered by moderate heat shock and Vibrio anguillarum, but not by V. splendidus or Micrococcus lysodeikticus
Cellura, C., Toubiana, M., Parrinello, N., & Roch, P. G. (2006) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2005.12.009 · Cited by 120
Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens
Chelvarajan, R. L., Collins, S. M., Doubinskaia, I. E., Goes, S. W., Willigen, J. V., Flanagan, D. L., de Villiers, W. J. S., Bryson, J. S., & Bondada, S. (2004) · Journal of Leukocyte Biology · doi:10.1189/jlb.0403179 · Cited by 118
“To determine if the failure of neonates to respond to TI Ag was a result of a deficiency in the production of cytokines by neonatal M , we stimulated splenic M with LPS, which is not only a TI Ag but is also a potent stimulator of M [8, 20].”
Method

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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