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*
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892-1360; and
Division of Molecular and Genetic Medicine, University of Sheffield, Sheffield, United Kingdom
A number of pathogens induce immature dendritic cells (iDC) to
migrate to lymphoid organs where, as mature DC (mDC), they serve as
efficient APC. We hypothesized that pathogen recognition by iDC is
mediated by Toll-like receptors (TLRs), and asked which TLRs are
expressed during the progression of monocytes to mDC. We first measured
mRNA levels for TLRs 15 and MD2 (a protein required for TLR4
function) by Northern analysis. For most TLRs, message expression
decreased severalfold as monocytes differentiated into iDC, but
opposing this trend, TLR3 and MD2 showed marked increases during iDC
formation. When iDC were induced to mature with LPS or TNF-
,
expression of most TLRs transiently increased and then nearly
disappeared. Stimulation of iDC, but not mDC, with LPS resulted in the
activation of IL-1 receptor-associated kinase, an early component in
the TLR signaling pathway, strongly suggesting that LPS signals through
a TLR. Surface expression of TLRs 1 and 4, as measured by mAb binding,
was very low, corresponding to a few thousand molecules per cell in
monocytes, and a few hundred or less in iDC. We conclude that TLRs are
expressed in iDC and are involved in responses to at least one
pathogen-derived substance, LPS. If TLR4 is solely responsible for LPS
signaling in humans, as it is in mice, then its extremely low surface
expression implies that it is a very efficient signal transducer in
iDC.
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