Inflammation is inseparable part of different diseases especially
cancer and autoimmunity. During
inflammation process
toll like receptor 4(TLR4) responds to
lipopolysaccharide (LPS), one of the bacterial components, and TLR4 signaling leads to interleukine-1 receptor associated kinase-1 (IRAK1) and
tumor necrosis factor (
TNF) receptor associated factor6 (
TRAF6) activation which ultimately results in nuclear factor- ĸB (NF-ĸB) activation as the main
transcription factor of inflammatory
cytokines. Conversely, NF-ĸB over activation induces miR-146a in innate immune cells which can consequently reduce
TRAF6, IRAK1, and NF-ĸB activation in a negative feedback.
G2013 is a novel designed non-steroidal anti-inflammatory
drug (
NSAID) which was recently shown to be effective in
experimental autoimmune encephalomyelitis (EAE) mouse model. The aim of this study was to evaluate
G2013 effects on inflammatory (IRAK1 and
TRAF6) and anti-inflammatory (miR-146a) factors of TLR4 signaling pathway. For this purpose, cytotoxicity of
G2013 has been evaluated by MTT assay. Expression level of miR-146a in PBMCs and IRAK1 along with
TRAF6 in HEK-293 TLR4 cells have been determined using real time PCR. Our results showed that IC50 of
G2013 was 25μg/ml, thus 5 and 25 μg/ml concentrations used for further treatments as low dose and high dose concentrations. Our results showed that IRAK1 expression reduced between 5 to 8 fold
after treatment by
G2013 in a dose dependent manner (p<0.001). In parallel
TRAF6 expression declined between 3 to 10 fold dose dependently (p<0.05). However, miR-146a expression was not affected
after treatment with low dose and high dose of
G2013. In conclusion our data showed that
G2013 can regulate TLR4 signaling pathway during
inflammation by reducing downstream signaling molecules, IRAK1 and
TRAF6 without altering miR-146a expression.