L'action ambivalente de l'agent anti-cancéreux 5-Fluorouracile sur les cellules myéloïdes immunosuppressives sous contrôle de l'acide docosahexaénoïque : Rôle de l'inflammasome NLRP3 et de la voie JNK dans la sécrétion de l'IL-1beta

Abstract : A limitation to 5-Fluorouracil (5-FU) anti-cancer efficacy relies on the secretion of IL-1β by myeloid-derived suppressor cells (MDSC) according to a previous pre-clinical report. The release of mature IL-1β originates from 5 FU mediated NLRP3 activation with increased caspase-1 activity in MDSC and sustains tumor growth recovery in 5 FU treated mice. Docosahexaenoic acid (DHA) belongs to omega-3 fatty acid family and harbors both anti cancer and anti inflammatory properties which might could improve 5 FU chemotherapy. Here, we demonstrate that DHA inhibits 5 FU induced IL 1β secretion produced by a MDSC cell line (MSC-2). In tumor-bearing mice treated with 5 FU, we showed that a DHA enriched diet reduces circulating IL 1β concentration and tumor recurrence after 5 FU injection. 5 FU treatment led to JNK activation in MDSC and JNK inhibitor SP600125 decreased IL 1β secretion. Moreover, DHA was able to counteract 5 FU mediated JNK activation in MDSC leading to the drop of IL 1β release. In addition, we showed that DHA supplementation in 5 FU exposed MDSC decreases caspase-1 activity along with a modification of the interactions between NLRP3 and caspase-1, ASC or β arrestin-2. Unexpectedly, the regulation of caspase-1 activity by DHA was independent of JNK which suggests that DHA could control IL 1β secretion through both NLRP3 inflammasome and JNK pathway. Interestingly, we found a negative correlation between DHA content in plasma and the induction of circulating IL 1β level or caspase-1 activity in patients treated with 5 FU based chemotherapy.Together, these data provide new insights on the regulation of IL 1β secretion by DHA and its potential benefit in 5-FU based chemotherapy.
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Adélie Dumont. L'action ambivalente de l'agent anti-cancéreux 5-Fluorouracile sur les cellules myéloïdes immunosuppressives sous contrôle de l'acide docosahexaénoïque : Rôle de l'inflammasome NLRP3 et de la voie JNK dans la sécrétion de l'IL-1beta. Physiologie [q-bio.TO]. Université Bourgogne Franche-Comté, 2018. Français. ⟨NNT : 2018UBFCI013⟩. ⟨tel-02139419⟩

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