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Involvement of toll-like receptor (TLR) 2 and TLR4 in cell activation by mannuronic acid polymers

Trude H Flo1, Liv Ryan, Eicke Latz

  • 1Institute of Cancer Research and Molecular Biology and the Institute of Biotechnology, Norwegian University of Science and Technology, 7489 Trondheim, Norway.

The Journal of Biological Chemistry
|June 29, 2002
PubMed

Insights

The Pseudomonas aeruginosa alginate capsule (poly-M) stimulates immune cells. Both Toll-like receptor (TLR) 2 and TLR4 are involved in this activation, with TLR4 being crucial for primary macrophages.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • The Pseudomonas aeruginosa alginate capsule, primarily poly-mannuronic acid (poly-M), possesses immunostimulating properties.
  • Poly-M activates human monocytes for cytokine production in a CD14-dependent pathway, similar to lipopolysaccharide.

Purpose of the Study:

  • To investigate the involvement of Toll-like receptor (TLR) 2 and TLR4 in the immune response to poly-M.
  • To elucidate the specific roles of TLR2 and TLR4 in mediating cellular activation by poly-M.

Main Methods:

  • Utilized blocking antibodies against TLR2 and TLR4 to assess their impact on tumor necrosis factor (TNF) production in human monocytes.
  • Employed transient transfection of HEK293 cells with CD14, TLR2, and TLR4/MD-2 to study receptor-mediated activation.
  • Analyzed responses in macrophages from TLR4 mutant (C3H/HeJ) and TLR4 knockout mice, as well as TLR2 knockout macrophages.

Main Results:

  • Combined blocking antibodies against TLR2 and TLR4 significantly inhibited poly-M-induced TNF production in human monocytes.
  • HEK293 cells expressing membrane CD14 with either TLR2 or TLR4/MD-2 demonstrated activation by poly-M.
  • Macrophages from TLR4-deficient mice showed no response to poly-M, while TLR2 knockout macrophages exhibited reduced TNF release compared to wild-type.

Conclusions:

  • Both TLR2 and TLR4 play a role in mediating cellular activation by poly-M.
  • TLR4 appears to be essential for the response to poly-M in primary murine macrophages.

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