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Toll-like receptor 4 functions intracellularly in human coronary artery endothelial cells: Roles of lbp and scd14 in mediating lps-responses

Academic Article
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Overview

authors

  • Dunzendorfer, S.
  • Lee, H. K.
  • Soldau, K.
  • Tobias, Peter

publication date

  • May 2004

journal

  • FASEB Journal  Journal

abstract

  • Endothelial cells are activated by microbial agonists through Toll-like receptors (TLRs) to express inflammatory mediators; this is of significance in acute as well as chronic inflammatory states such as septic shock and atherosclerosis, respectively. We investigated mechanisms of lipopolysaccharide (LPS)-induced cell activation in human coronary artery endothelial cells (HCAEC) using a combination of FACS, confocal microscopy, RT-PCR, and functional assays. We found that TLR4, in contrast to TLR2, is not only located intracellularly but also functions intracellularly. That being the case, internalization of LPS is required for activation. We further characterized the HCAEC LPS uptake system and found that HCAEC exhibit an effective LPS uptake only in the presence of LPS binding protein (LBP). In addition to its function as a catalyst for LPS-CD14 complex formation, LBP enables HCAEC activation at low LPS concentrations by facilitating the uptake, and therefore delivery, of LPS-CD14 complexes to intracellular TLR4-MD-2. LBP-dependent uptake involves a scavenger receptor pathway. Our findings may be of pathophysiological relevance in the initial response of the organism to infection. Results further suggest that LBP levels, which vary as LBP is an acute phase reactant, could be relevant to initiating inflammatory responses in the vasculature in response to chronic or recurring low LPS.

subject areas

  • Acute-Phase Proteins
  • Acute-Phase Reaction
  • Adult
  • Animals
  • Antigens, Neoplasm
  • Antigens, Surface
  • Carrier Proteins
  • Cell Compartmentation
  • Cells, Cultured
  • Coronary Vessels
  • Endothelial Cells
  • Endothelium, Vascular
  • Flow Cytometry
  • Glycolipids
  • Humans
  • Intracellular Fluid
  • Lipid A
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Macromolecular Substances
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes
  • RNA, Messenger
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Receptors, Scavenger
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Umbilical Veins
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Research

keywords

  • endothelium
  • endotoxin
  • innate immunity
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Identity

International Standard Serial Number (ISSN)

  • 0892-6638

Digital Object Identifier (DOI)

  • 10.1096/fj.03-1263fje

PubMed ID

  • 15132988
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Additional Document Info

start page

  • 1117

end page

  • 1119

volume

  • 18

issue

  • 10

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