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

, Mots clefs : DHA, 5-FU, MDSC, NLRP3, IL-1?

, Chez des souris porteuses de tumeurs traitées par 5-FU, nous avons montré qu'un régime alimentaire enrichi en DHA réduit la concentration d'IL-1? circulante et la récidive tumorale après une injection de 5-FU. Le traitement par 5-FU conduit à l'activation de JNK dans les MDSC et l'inhibiteur de JNK SP600125 diminue la sécrétion d'IL-1?. De plus, le DHA est capable de contrecarrer l'activation de JNK induite par 5-FU dans les MDSC, entraînant la chute de la libération de l'IL-1?. De plus, nous avons montré que la supplémentation en DHA dans les MDSC exposées au 5 FU diminuait l'activité de la caspase-1 ainsi que la modification des interactions entre NLRP3 et la caspase-1, ASC ou ?-arrestine-2. De manière inattendue, la régulation de l'activité de la caspase-1 par le DHA était indépendante de JNK, ce qui suggère que le DHA pourrait contrôler la sécrétion de l'IL-1? par le biais de l'inflammasome NLRP3 et de la voie JNK. Enfin, nous avons trouvé une corrélation négative entre la teneur en DHA, Selon une étude précédente, une limitation à l'efficacité anticancéreuse du 5-Fluorouracile (5-FU) repose sur la sécrétion d'IL-1? par des cellules myéloïdes immunosuppressives (MDSC)

, L'ensemble de ces données fournissent de nouvelles informations sur la régulation de la sécrétion de l'IL-1? par le DHA et son bénéfice potentiel dans la chimiothérapie à base de, p.5

, IL-1?, JNK A limitation to 5-Fluorouracil (5-FU) anti-cancer efficacy relies on the secretion of IL-1? by myeloid-derived suppressor cells (MDSC) according to a previous pre-clinical report. The release of mature IL-1? 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-1? 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-1? concentration and tumor recurrence after 5-FU injection, The ambivalent action of the anti-cancer agent 5-Fluorouracil on myeloid derived suppressor cells under the control of docosahexaenoic acid: Role of the NLRP3 inflammasome and the JNK pathway in IL-1? secretion Keywords: DHA, 5-FU, MDSC, NLRP3

. Moreover, 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 ?-arrestin-2. Unexpectedly, the regulation of caspase-1 activity by DHA was independent of JNK which suggests that DHA could control IL-1? 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-1? level or caspase-1, DHA was able to counteract 5-FU-mediated JNK activation in MDSC leading to the drop of IL-1? release

, Together, these data provide new insights on the regulation of IL-1? secretion by DHA and its potential benefit in 5-FU-based chemotherapy