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observation that will be used to advantage in probing the role of
ellagitannins in immunostimulation (see Section 6.4.2) (Hoshino et al. ,
1999). Interestingly, TLR4 knockout mice showed an immunological
response to whole E. coli similar to that observed with normal mice,
suggesting that there are other receptors involved (Evans et al. , 1993). It
is now known that there are other bacterial components including
lipoprotein, peptidoglycan, bacterial DNA with a CpG sequence,
flagellin, and fimbriae, which can act as antigens through other TLR
members such as TLR2, TLR5, or TLR9 (Takeuchi et al. , 1999,
Frendeus et al. , 2001, Hayashi et al. , 2001, Hemmi et al. , 2000).
Furthermore, some bacteria such as the Gram-negative Porphyromonas
gingivalis with highly heterogeneous LPS use both TLR2 and TLR4 for
recognition (Shimazu et al. , 1999).
LPS circulating in an infected host is first recognized by the serum
protein lipopolysaccharide binding protein (LBP), a 60kDa carrier
peptide with a very high affinity for the lipid A portion of LPS
(K d varying between 1 to 58 nM) (Schumann et al. , 1990, Tobias et al. ,
1989, Gazzano-Santoro et al. , 1994). LBP, an acute-phase protein,
functions as an opsonin (binding enhancer for receptors) that aids in the
recognition of LPS by macrophages through binding to the surface of
bacteria or to the lipid A segment of LPS that is presented by
erythrocytes (Darveau et al. , 2004). Without infectious microbes in the
serum, LBP levels remain low, but after infection, they are rapidly
elevated by the liver, lungs, kidneys, and heart.
Once bound, LPS is transported by LBP to either the soluble
(sCD14) or the membrane-anchored CD14 receptor (mCD14), which is
attached to the cell membrane by a glycosylphosphatidylinositol (GPI)
group (Solomon et al. , 1998, Wright, 1995, Arditi et al. , 1993). The
55kDa glycoprotein CD14 was the first identified component of the LPS
receptor system (Wright et al. , 1990a). The soluble CD14 glycoprotein
mediates recognition by cells such as endothelial cells that lack the
membrane bound form of the receptor. The level of sCD14 is
substantially increased in septic shock patients. Membrane bound CD14
is expressed mainly on myeloid cells, including macrophages,
monocytes, and granulocytes, and some other cells such as liver
parenchymal cells, gingival fibroblasts, and B cells. Mice lacking the
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