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The equine TLR4/MD-2 complex mediates recognition of lipopolysaccharide from Rhodobacter sphaeroides as an agonist.
Abstract: Lipopolysaccharide (LPS) antagonists inhibit the response of inflammatory cells to LPS, presumably by competitive inhibition, and may be of therapeutic value in the treatment of endotoxemia and sepsis. The inhibitory effects of some LPS antagonists are restricted to certain host species, however, as the same molecules can have significant endotoxic activity in other species. This species-specific recognition appears to be mediated by Toll-like receptor 4 (TLR4) and/or MD-2. We have shown previously that LPS from Rhodobacter sphaeroides ( RsLPS) is an LPS antagonist in human cells but an agonist (or LPS mimetic) in equine cells. In the present study, HEK293 cells were transfected with combinations of human and equine CD14, TLR4 and MD-2, and incubated with either RsLPS or with LPS from Escherichia coli as an endotoxin control. NF-kappaB activation was measured in a dual luciferase assay as an indicator of cellular activation. Our results indicate that E. colic LPS activated NF-kappaB in cells transfected with all combinations of the three receptor proteins, whereas RsLPS activated NF-kappaB only in cells expressing the single combination of equine TLR4 and equine MD-2. We conclude that the TLR4/MD-2 complex is responsible for recognition of RsLPS as an agonist in equine cells.
Publication Date: 2007-10-25 PubMed ID: 17956942DOI: 10.1177/0968051907083193Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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The study documents the influence of a specific bacterial lipopolysaccharide (LPS) called RsLPS on the activation of NF-KappaB, a key protein in inflammation processes, in horse cells, via receptors TLR4 and MD-2. The results suggest that this molecule can specifically trigger an inflammatory response in horse cells, indicating a species-specific immune reaction.
Background on the Study
- The study begins by discussing the role of lipopolysaccharide (LPS), a molecule found in the outer membrane of certain bacteria, which can trigger an immune response.
- The researchers highlight how LPS antagonists (molecules that inhibit the activity of LPS) can be used therapeutically to treat conditions such as endotoxemia and sepsis, which are caused by an overactive immune response against LPS.
- However, the effect of these LPS antagonists can vary depending on the host species, implying a species-specific recognition of LPS.
The Role of RsLPS
- The researchers previously discovered that LPS from Rhodobacter sphaeroides (RsLPS) inhibits an immune response in human cells, but triggers one in equine (horse) cells. This suggests RsLPS is a species-specific agonist.
Experimental Procedure
- For this study, HEK293 cells (a common cell line in biological research) were manipulated to produce either human or equine versions of three specific proteins: CD14, TLR4, and MD-2.
- These proteins are known to be involved in the recognition and response to LPS in cells.
- The cells were then exposed to RsLPS and to LPS from Escherichia coli (a common source of LPS), and the researchers measured the activation of NF-kappaB, a protein involved in the inflammatory response.
Key Findings
- LPS from Escherichia coli activated NF-kappaB in all cell lines, suggesting that this LPS is recognized by a variety of cellular receptors.
- However, RsLPS only triggered NF-KappaB activation in cells expressing the equine versions of TLR4 and MD-2, indicating that this specific LPS is recognized by the horse’s specific receptor complex.
- The researchers thus concluded that the TLR4/MD-2 complex in equine cells mediates recognition of RsLPS as an agonist.
Cite This Article
APA
Lohmann KL, Vandenplas ML, Barton MH, Bryant CE, Moore JN.
(2007).
The equine TLR4/MD-2 complex mediates recognition of lipopolysaccharide from Rhodobacter sphaeroides as an agonist.
J Endotoxin Res, 13(4), 235-242.
https://doi.org/10.1177/0968051907083193 Publication
Researcher Affiliations
- Department of Large Animal Medicine, University of Georgia, Athens, Georgia, USA. k.lohmann@usask.ca
MeSH Terms
- Animals
- Cell Line
- Horses
- Humans
- Lipopolysaccharide Receptors / genetics
- Lipopolysaccharides / isolation & purification
- Lipopolysaccharides / pharmacology
- Microtubule-Associated Proteins / genetics
- NF-kappa B / physiology
- Reverse Transcriptase Polymerase Chain Reaction
- Rhodobacter sphaeroides
- Toll-Like Receptor 4 / genetics
- Toll-Like Receptor 4 / physiology
- Transcription Factors / genetics
- Transfection
Citations
This article has been cited 14 times.- Mukhopadhyay A, Cook SR, SanMiguel P, Ekenstedt KJ, Taylor SD. TLR4 and MD2 variation among horses with differential TNFα baseline concentrations and response to intravenous lipopolysaccharide infusion. Sci Rep 2023 Jan 27;13(1):1486.
- Heine H, Zamyatina A. Therapeutic Targeting of TLR4 for Inflammation, Infection, and Cancer: A Perspective for Disaccharide Lipid A Mimetics. Pharmaceuticals (Basel) 2022 Dec 23;16(1).
- Zhao J, Guo S, Schrodi SJ, He D. Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications. Front Immunol 2021;12:790122.
- Sekiguchi F, Kawabata A. Role of HMGB1 in Chemotherapy-Induced Peripheral Neuropathy. Int J Mol Sci 2020 Dec 31;22(1).
- Di Lorenzo F, Kubik Ł, Oblak A, Lorè NI, Cigana C, Lanzetta R, Parrilli M, Hamad MA, De Soyza A, Silipo A, Jerala R, Bragonzi A, Valvano MA, Martín-Santamaría S, Molinaro A. Activation of Human Toll-like Receptor 4 (TLR4)·Myeloid Differentiation Factor 2 (MD-2) by Hypoacylated Lipopolysaccharide from a Clinical Isolate of Burkholderia cenocepacia. J Biol Chem 2015 Aug 28;290(35):21305-19.
- Lonez C, Irvine KL, Pizzuto M, Schmidt BI, Gay NJ, Ruysschaert JM, Gangloff M, Bryant CE. Critical residues involved in Toll-like receptor 4 activation by cationic lipid nanocarriers are not located at the lipopolysaccharide-binding interface. Cell Mol Life Sci 2015 Oct;72(20):3971-82.
- Anwar MA, Panneerselvam S, Shah M, Choi S. Insights into the species-specific TLR4 signaling mechanism in response to Rhodobacter sphaeroides lipid A detection. Sci Rep 2015 Jan 7;5:7657.
- Irvine KL, Gangloff M, Walsh CM, Spring DR, Gay NJ, Bryant CE. Identification of key residues that confer Rhodobacter sphaeroides LPS activity at horse TLR4/MD-2. PLoS One 2014;9(5):e98776.
- Scior T, Lozano-Aponte J, Figueroa-Vazquez V, Yunes-Rojas JA, Zähringer U, Alexander C. Three-dimensional mapping of differential amino acids of human, murine, canine and equine TLR4/MD-2 receptor complexes conferring endotoxic activation by lipid A, antagonism by Eritoran and species-dependent activities of Lipid IVA in the mammalian LPS sensor system. Comput Struct Biotechnol J 2013;7:e201305003.
- Zamani F, Zare Shahneh F, Aghebati-Maleki L, Baradaran B. Induction of CD14 Expression and Differentiation to Monocytes or Mature Macrophages in Promyelocytic Cell Lines: New Approach. Adv Pharm Bull 2013;3(2):329-32.
- Lu Z, Li Y, Samuvel DJ, Jin J, Zhang X, Lopes-Virella MF, Huang Y. MD-2 is involved in the stimulation of matrix metalloproteinase-1 expression by interferon-γ and high glucose in mononuclear cells - a potential role of MD-2 in Toll-like receptor 4-independent signalling. Immunology 2013 Nov;140(3):301-13.
- Werners AH, Bryant CE. Pattern recognition receptors in equine endotoxaemia and sepsis. Equine Vet J 2012 Jul;44(4):490-8.
- Govindaraj RG, Manavalan B, Basith S, Choi S. Comparative analysis of species-specific ligand recognition in Toll-like receptor 8 signaling: a hypothesis. PLoS One 2011;6(9):e25118.
- Bai M, Sun R, Cao B, Feng J, Wang J. Monocyte-related cytokines/chemokines in cerebral ischemic stroke. CNS Neurosci Ther 2023 Dec;29(12):3693-3712.
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