Biology Reference
In-Depth Information
CD14 receptor molecule showed little-to-no response when injected with
otherwise lethal doses of either LPS or whole
E. coli
(Haziot
et al.
,
1996). In humans injected with LPS, CD14 antibodies partially reduced
the clinical symptoms and cytokine response of sepsis (Verbon
et al.
,
2001). These data, and the fact that the CD14 protein lacks an
intracellular domain necessary for signal transduction, suggested that
there was another transmembrane protein that was part of the LPS
receptor system. This elusive signal transmitting protein was, in fact,
identified as TLR4 and through an as yet unidentified interaction, CD14
helps transfer LPS to this receptor/signaling molecule. In addition, TLR4
appears to require an accessory protein called MD-2 in order to engage
LPS (Shimazu
et al.
, 1999). MD-2, a secreted glycoprotein, forms a
complex with the membrane bound TLR4 for effective recognition of
this ligand. MD-2 knockout mice did not induce up-regulation of TNFα
in response to LPS, demonstrating that MD-2 is a necessary adaptor
component for signaling (Nagai
et al.
, 2002).
Malhotra also has suggested that cell-surface adhesion molecules
known as selectins may act as low-affinity receptors for LPS, also
through the lipid A recognition site, when it is present in high
concentrations. CD14 knockout mice have shown a CD14-dependence to
macrophage activation at concentrations lower than 10 ng/mL of LPS,
but not at greater than 100 ng/mL of LPS (Loppnow
et al.
, 1995,
Malhotra and Bird, 1997). At the higher concentrations, the CD14-
lacking mice exhibited a response similar to that of the wild-type mice.
P-selectin and L-selectin have been reported to bind LPS (Malhotra
et
al.
, 1996, 1998). In addition, the use of antibodies against both receptors
significantly reduced their ability to bind fluorescently labeled LPS and
decreases the levels of both TNFα mRNA and oxygen radicals formed in
neutrophils. These observations have lead Malhotra's group to suggest
that the selectins act as LPS receptors at high LPS concentrations.
Moesin, a 78 kDa cell-surface protein with both a diverse biological
activity profile and signal transduction capability, may also be involved
in the recognition of LPS. An antimoesin monoclonal antibody
completely blocked LPS induced TNFα release without impeding LPS-
to-CD14 binding (Tohme
et al.
, 1999, Iontcheva
et al.
, 2004). Van Dyke
and co-workers have shown that moesin is able to bind LPS, CD14, and
