1) Gram-negative bacteria release
lipopolysaccharide (LPS; endotoxin) from the outer membrane of their cell wall.
2) The LPS binds to a pair of TLR-4s on defense cells such as macrophages and dendritic cells. LPS also binds to LPS-binding protein in the plasma and tissue fluid. The LPS-binding protein promotes the binding of LPS to the CD14 receptors. At that point the LPS-binding protein comes off and the LPS-CD14 bind to TLR-4.
3) The binding of LPS to TLR-4 enables regulatory molecules within the cell - Mal, MyD88, Tram, and Trif - to trigger reactions that activate a master regulator of inflammation called NF-kappa B. Activated NF-kappa B enters the cell's nucleus and switches on genes coding for cytokines such as:
4) Cytokine genes are transcribed into mRNA molecules that goe to the cytoplasm to be translated into inflammatory cytokines that are subsequently secreted from the cell.
a. Interleukin-1 (IL-1) and Tumor necrosis factor-alpha (TNF-alpha): enhance inflammatory responses;
b. Interleukin-8 (IL-8): aids in the ability of white blood cells to leave the blood vessels and enter the tissue; a chemoattractant for phagocytes;
c. Interleukin-6 (IL-6) promotes B-lymphocyte activity; and
d. Interleukin-12 (IL-12): promotes T-lymphocyte activity. (5)
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Updated: Sept. 2008
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