CD14 cooperates with another acute phase protein, LBP
(LPS-binding protein), which binds LPS
and transfers it to CD14 (1-3, 17). LPS can be further
transferred from CD14 to the TLR4/MD2
complex on the cell surface (1). LPS causes signaling via
clustering of LPS-bound CD14/TLR4/
MD2 complexes within cholesterol-rich lipid rafts (1). These
signals induce production of
inflammatory cytokines and other inflammatory proteins (18,
19). When uncoordinated, the
signals contribute to septic shock (1). CD14 potentiates
TLR-mediated signals triggered by
microbe-derived ligands other than LPS, including TLR2
activation by polymeric peptidoglycan,
gram-positive bacterial lipoteichoic acid, or mycobacterial
lipoarabinomannan (1, 20). It
increases uptake and trafficking of the viral TLR3 ligand,
poly(I:C) (1, 20). In the lungs, CD14
binds phosphoinositides and surfactant proteins, such as
SP-A and SP-D, via interaction of
lipids with the CD14 LPS binding site (21, 22). CD14 may
also bind ICAM-3 on apoptotic
leukocytes and induce phagocytosis (23).
High concentrations of sCD14 may inhibit LPS-mediated
responses by competing for binding
to mCD14 (24). In the presence of LBP, however, sCD14 can
also potentiate LPS responses or
help cells to clear circulating LPS, whether or not the
cells express mCD14 (16-19). At low
concentrations of LPS, both sCD14 and mCD14 can mediate
endothelial cell responses such as
upregulation of E-selectin, while response to intermediate
concentrations of LPS requires
mCD14 (16). Circulating sCD14, especially presepsin, is
increased in sepsis and may correlate
with severity (11, 12). sCD14 may be increased as compared
to normal circulating sCD14 in
some autoimmune diseases, such as multiple sclerosis and
rheumatoid arthritis, but decreased
in others, such as Crohn's disease (25-27). sCD14 can also
modulate inflammation-driven insulin
resistance (28).
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