LPS response and endotoxin tolerance in Flt-3L-induced bone marrow-derived dendritic cells |
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Authors: | Patenaude Julie D'Elia Michele Côté-Maurais Guillaume Bernier Jacques |
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Affiliation: | INRS-Institut Armand-Frappier, 531 boul. des Prairies, Laval, Québec, Canada |
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Abstract: | Fms-like tyrosine kinase-3 ligand (Flt-3L) stimulates the differentiation of bone marrow cells into dendritic cells (DCs) and was used as an adjuvant therapy in the experimental model of burn wound sepsis. In this study, we describe the phenotypical characteristics of an Flt-3L-dependent DC culture (FLDC) system following LPS stimulation, which induces an inflammatory response, and after a second LPS stimulation, which induces tolerance. Priming of FLDCs with LPS via TLR4 has been shown to induce the activation of all three mitogen-activated protein kinase (MAPK) families and enhance NF-κB complex translocation into the nucleus. Stimulated FLDCs express all maturation markers and exhibit an increase in IL-12p40 production and to a lesser extent, IL-10 production. In contrast, LPS stimulation of tolerized FLDCs was not associated with TLR4 up-regulation and led to MAPK inhibition. The decrease in p38 and JNK activation was correlated with an impairment of IL-12p40 production. Endotoxin tolerance in FLDCs was associated with enhanced ERK1/2 activation, an increase in MKP-1 phosphatase expression, a decrease in NF-κB translocation to the nucleus and an increase in IL-10 production. Overall, DCs generated from bone marrow with Flt-3 ligand have similar characteristics to DC subtypes found in the steady state in vivo, which can acquire endotoxin tolerance in some circumstances. |
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Keywords: | Abbreviations: APC, antigen-presenting cells DCs, dendritic cells cDCs, conventional DCs Flt-3L, Fms-like tyrosine kinase-3 ligand FLDCs, Flt-3L-induced DCs GM-DCs, GM-CSF/IL-4-induced DCs IRAK-M, IL-1R-associated kinase-M LPS, lipopolysaccharides MKP-1, mitogen-kinase phosphatase-1 MAPK, mitogen activated kinase TLR-4, toll-like receptor-4 Th, T helper SOCS, suppressor of cytokine signaling |
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