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10.1371/journal.pone.0135444

http://scihub22266oqcxt.onion/10.1371/journal.pone.0135444
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C4556692!4556692!26327508
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suck abstract from ncbi


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pmid26327508      PLoS+One 2015 ; 10 (9): ä
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  • In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates Antitumor Immune Response #MMPMID26327508
  • Braun FCM; van den Brandt J; Thomas S; Lange S; Schrank J; Gand C; Przybylski GK; Schmoeckel K; Bröker BM; Schmidt CA; Grabarczyk P
  • PLoS One 2015[]; 10 (9): ä PMID26327508show ga
  • A20 is an ubiquitin-editing enzyme that ensures the transient nature of inflammatory signaling pathways induced by cytokines like TNF-? and IL-1 or pathogens via Toll-like receptor (TLR) pathways. It has been identified as a negative regulator of dendritic cell (DC) maturation and attenuator of their immunostimulatory properties. Ex vivo A20-depleted dendritic cells showed enhanced expression of pro-inflammatory cytokines and costimulatory molecules, which resulted in hyperactivation of tumor-infiltrating T lymphocytes and inhibition of regulatory T cells. In the present study, we demonstrate that a synthetic molecule consisting of a CpG oligonucleotide TLR9 agonist linked to A20-specific siRNAs silences its expression in TLR9+ mouse dendritic cells in vitro and in vivo. In the B16 mouse melanoma tumor model, silencing of A20 enhances the CpG-triggered induction of NF?B activity followed by elevated expression of IL-6, TNF-? and IL-12. This leads to potentiated antitumor immune responses manifested by increased numbers of tumor-specific cytotoxic T cells, high levels of tumor cell apoptosis and delayed tumor growth. Our findings confirm the central role of A20 in controlling the immunostimulatory potency of DCs and provide a strategy for simultaneous A20 silencing and TLR activation in vivo.
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