Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=26327508
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
In Vivo Silencing of A20 via TLR9-Mediated Targeted SiRNA Delivery Potentiates
Antitumor Immune Response
#MMPMID26327508
Braun FC
; 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
): e0135444
PMID26327508
show 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.
|*Gene Silencing
[MESH]
|Animals
[MESH]
|Blotting, Western
[MESH]
|Cell Line, Tumor
[MESH]
|Cysteine Endopeptidases/*drug effects
[MESH]
|Cytokines/metabolism
[MESH]
|Dendritic Cells/drug effects/immunology
[MESH]
|Female
[MESH]
|Immunity, Humoral/drug effects/physiology
[MESH]
|Intracellular Signaling Peptides and Proteins/*drug effects
[MESH]
free
free
free
