Regulation of Toll-like receptors in human monocytes and dendritic cells

A number of pathogens induce immature dendritic cells (iDC) to migrate to l ymphoid organs where, as mature DC (mDC), they serve as efficient APC, We h ypothesized that pathogen recognition by iDC is mediated by Toll-like recep tors (TLRs), and asked which TLRs are expressed during the progression of m onocytes to mDC, We first measured mRNA levels for TLRs 1-5 and MD2 (a prot ein required for TLR4 function) by Northern analysis. For most TLRs, messag e expression decreased severalfold as monocytes differentiated into IDC, bu t opposing this trend, TLR3 and MD2 showed marked increases during iDC form ation. When iDC were induced to mature with LPS or TNF-alpha, expression of most TLRs transiently increased and then nearly disappeared. Stimulation o f iDC, but not mDC, with LPS resulted in the activation of IL-1 receptor-as sociated 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 thousa nd molecules per cell in monocytes, and a few hundred or less in IDC, We co nclude that TLRs are expressed in iDC and are involved in responses to at l east 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.