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Blood Cells Mol Dis. 1999 Oct-Dec;25(5-6):328-38.

Analysis of Tlr4-mediated LPS signal transduction in macrophages by mutational modification of the receptor.

Author information

1
Howard Hughes Medical Institute, Dallas, TX 75235-9050, USA.

Erratum in

  • Blood Cells Mol Dis 2000 Feb;26(1):9.

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 10(4) 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 an ectodomain [corrected], 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.

PMID:
10660480
DOI:
10.1006/bcmd.1999.0262
[Indexed for MEDLINE]

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