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Abstract
Abstract Danger Signals induce dendritic cells (DCs) to mature and present antigen in a pro-inflammatory context. When remaining immature however, DCs confer tolerance. Hence the need for new protocols inducing tolerogenic DCs. We assessed the effects of ethyl pyruvate (EP), ester derivative of pyruvate with anti-inflammatory properties, on DC responses. We found that EP (10mM) abolished pro-inflammatory cytokine induction (IL-12, TNFa, IL-6) by the TLR ligand and strong DC activator LPS in bone marrow-derived dendritic cells (BMDCs) at 8, 24, 48 and 72h post-stimulation. Furthermore, EP inhibited the IFN-I response and the anti-inflammatory cytokine IL-10 induced by LPS stimulation. Determining the effects of EP on BMDC viability with a dose titration response showed that EP (10mM) strongly inhibited in vitro DC activation without inducing death. Moreover, EP could prevent LPS-induced killing that normally occurs 72h post-stimulation. EP also decreased the up-regulation of BMDC surface MHC-II and co-stimulatory molecules, suggesting a role in inhibiting antigen presentation. Investigating the mechanism of action, EP decreased Erk and JNK phosphorylation but not p38 phosphorylation. Our results indicate that EP inhibits most of the biological responses of DCs to LPS. We are currently examining further the molecular mechanisms of EP’s action in BMDCs to highlight novel targets to inhibit DC activation.
Published Version
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