The data confirm previously published studies at other centers. “
“The activation of TLRs expressed by macrophages or DCs, in the long run, leads to persistently impaired functionality. TLR signals activate a wide range of negative feedback mechanisms; it is not known, however, which of these can lead to long-lasting tolerance for further stimulatory signals. In addition, it is not yet understood how the functionality of monocyte-derived DCs (MoDCs) is influenced in inflamed tissues by the continuous RAD001 solubility dmso presence of stimulatory

signals during their differentiation. Here we studied the role of a wide range of DC-inhibitory mechanisms in a simple and robust model of MoDC inactivation induced by early TLR signals during differentiation. We show that the activation-induced suppressor of cytokine signaling 1 (SOCS1), IL-10, STAT3, miR146a and CD150 (SLAM) molecules possessed short-term inhibitory effects on cytokine production but did not induce persistent DC inactivation. On the contrary, the LPS-induced IRAK-1 downregulation could alone lead to persistent MoDC inactivation. Studying cellular functions in line with the activation-induced

negative feedback mechanisms, we show that early activation of developing MoDCs allowed only a transient cytokine production that was followed by the downregulation of effector functions and the preservation of a tissue-resident non-migratory phenotype. In response to pathogen recognition or inflammatory Pifithrin-�� nmr mediators, steady-state tissue-resident DCs exit the inflamed tissues and transport peripheral antigens to secondary lymphoid organs, where DCs can initiate the adaptive immune response by triggering naïve T-cell activation. At the same

time, monocytes enter the inflamed tissues and give rise to phagocytic cells and APCs, including DCs, thereby compensating the rapid egress of the steady-state DC network 1–3. The newly differentiated monocyte-derived DCs (MoDCs) may act as local tissue resident APCs or as sources of inflammatory cytokines 4, 5. In addition, these cells might obtain the ability to migrate to peripheral lymphoid organs maintaining the activation of naïve T lymphocytes 2, 6. Human monocytes obtain DC-like features when maintained 2-hydroxyphytanoyl-CoA lyase in culture for 5–8 days in the presence of GM-CSF combined with IL-4 or other cytokines 7, 8. During their differentiation MoDCs downregulate CD14, upregulate CD1a and DC-SIGN and obtain the ability to express CCR7 upon activation that is required for migration towards lymphoid tissues. However, such differentiation of immature MoDCs is highly unlikely to occur in inflamed tissues where the developing cells constantly receive stimulatory signals due to the presence of microbial compounds, inflammatory mediators and tissue damage. It has been extensively documented that long-term activation leads to functional exhaustion of macrophages and DCs 9.