Anmerkungen:
Hinweis: Link zur Erstveröffentlichung URL: https://doi.org/10.1159/000495528
Beschreibung:
In response to GM-CSF or M-CSF, macrophages (MΦ) can acquire
pro- or anti-inflammatory properties, respectively. Given
the importance of CD14 and Toll-like receptor (TLR) 4 in
lipopolysaccharide (LPS)-induced signaling, we studied the
effect of anti-CD14 antibody mediated CD14 blockade on
LPS-induced cytokine production, signal transduction and
on the expression levels of CD14 and TLR4 in GM-MΦ and
M-MΦ. We found M-MΦ to express higher levels of both surface
antigens and to produce more interferon (IFN)-β and
interleukin-10, but less tumor necrosis factor (TNF)-α than
GM-MΦ. Blockage of CD14 at high LPS concentrations increased
the production of proinflammatory cytokines and
decreased that of IFN-β in M-MΦ but not in GM-MΦ. We
show that phosphorylation states of signaling molecules of
the MyD88 (myeloid differentiation primary response 88),
TRIF (TIR-domain-containing adapter-inducing IFN-β) and
MAPK (mitogen-activated protein kinase) pathways are not
altered in any way that would account for the cytokine overshoot
reaction. However, CD14 blockage in M-MΦ decreased
TLR4 and CD14 expression levels, regardless of the presence
of LPS, indicating that the loss of the surface molecules prevented
LPS from initiating TRIF signaling. As TNF-α synthesis
was even upregulated under these experimental conditions,
we suggest that TRIF is normally involved in restricting LPSinduced
TNF-α overproduction. Thus, surface CD14 plays a
decisive role in the biological response by determining LPSinduced
signaling.