Abstract
In mouse macrophages (RAW 264.7 cells), toll-like receptor 4 (Tlr4) is a limiting factor in lipopolysaccharide (LPS) signal transduction. The expression of only 1-2 X 104 copies of recombinant Tlr4 per cell enhances sensitivity to LPS, shifting the EC50 by 30-fold to the left. Expression of the Tlr4(Lps-d) isoform of Tlr4 (found in C3H/HeJ mice) shifts the EC50 2600- fold to the right, essentially abolishing LPS responses. A truncated form of Tlr4, lacking a cytoplasmic domain, exerts only a weak inhibitory effect on signal transduction. Similarly, the normal or Tlr4(Lps-d) forms of protein lacking a cytoplasmic domain, cause modest inhibition of LPS signaling. Manipulations of Tlr4 structure and expression cause changes in LPS sensitivity that range over 3 to 4 orders of magnitude. These findings support the view that Tlr4 is an integral component of a solitary pathway for LPS signal transduction in macrophages and permit inferences related to the mechanism of signaling and its blockade. (C) 1999 Academic Press.
Original language | English (US) |
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Pages (from-to) | 328-338 |
Number of pages | 11 |
Journal | Blood Cells, Molecules, and Diseases |
Volume | 25 |
Issue number | 6 |
DOIs | |
State | Published - 1999 |
Keywords
- Endotoxin
- Macrophage
- Mutagenesis
- Receptor
- Toll-like receptor 4
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Hematology
- Cell Biology