Article ID Journal Published Year Pages File Type
3355695 Immunology Letters 2012 11 Pages PDF
Abstract

BackgroundAs essential components of the innate immune system, dendritic cells (DCs) can interact directly with pathogens as well as participate in the adaptive immune response. In cells closely related to DCs such as macrophages and monocytes, prior exposure to minute amounts of endotoxin can lead to a refractory period where subsequent exposure to higher doses fails to induce an inflammatory response; little research has investigated this effect on DCs. This study tested if murine bone marrow-derived dendritic cells (BM-DCs) respond to endotoxin- and bacterial sonicate-induced tolerance by decreased inflammatory and increased anti-inflammatory response, and the role of IRAK-M, an intracellular negative regulator of TLR signaling, in this tolerance.ResultsTolerized BM-DCs exhibited a significant drop in TNF-α and IL-12p70 production and increased IL-10 expression compared to untolerized cells. BM-DCs also showed the ability to develop heterotolerance, in which the LPS exposure alone was able to induce tolerance to Helicobacter pylori sonicate and TLR2 agonist Pam3Cys. Furthermore, the expression of IRAK-M was increased after restimulation of tolerized BM-DCs as determined qPCR and Western blot. IRAK-M exhibited a suppressive effect on surface expression of major histocompatibilty complex class II (MHC II) and CD80 in LPS-tolerized BM-DCs. IL-10 expression in bacterial sonicate-tolerized IRAK-M−/− BM-DCs was altered as compared to wild type BM-DCs, with tolerance-induced expression of IL-10 mitigated in tolerized IRAK-M−/− BM-DCs.ConclusionAlong with endotoxin, bacterial sonicate is able to induce refractory tolerance in BM-DCs, and IRAK-M plays a role in modulating cell surface expression of MHC class II and CD80 and release of IL-10 during this tolerance.

► Bacterial sonicate is able to induce refractory tolerance in BM-DCs. ► IRAK-M, an intracellular inhibitor of NF-κB signaling, increases during this tolerance. ► IRAK-M suppresses MHC II and CD80 while promoting IL-10 expression.

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