Mycophenolic Acid Synergizing with Lipopolysaccharide to Induce Interleukin-1β Release via Activatio

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Background:The previous study showed that mycophenolic acid (MPA) synergizing with lipopolysaccharide (LPS) promoted interleukin (IL)-1β release,but the mechanism is unclear.This study aimed to investigate the mechanism of MPA synergizing with LPS to induce IL-1β release.Methods:Undiluted human blood cells,THP-1 human myeloid leukemia mononuclear cells (THP-1) cells,or monocytes were stimulated with LPS and treated with or without MPA,and the supatant IL-1β was detected by enzyme-linked immunosorbent assay.The mRNA levels of IL-1β were detected by real-time quantitative polymerase chain reaction.The intracellular protein levels of nuclear factor kappa B (NF-κB) phospho-p65 (p-p65),precursor interleukin-1β (pro-IL-1β),NOD-like receptor pyrin domain containing-3 (NLRP3),and cysteine aspartic acid-specific protease-1 (caspase-1) p20 in THP-1 cell were measured by West blot.Results:The MPA alone failed to induce IL-1β,whereas MPA synergized with LPS to increase IL-1β in a dose-dependent manner (685.00 ± 20.00 pg/ml in LPS + 5 μmol/L MPA group,P =0.035;742.00 ± 31.58 pg/ml in LPS + 25 μmol/L MPA group,P =0.017;1000.00 ± 65.59 pg/ml in LPS + 75 μmol/L MPA group,P=0.024;versus 408.00 ± 35.50 pg/ml in LPS group).MPA alone has no effect on the IL-1β mRNA expression,LPS induced the expression of IL-1β mRNA 2761 fold,and LPS + MPA increased the IL-1β expression 3018 fold,which had the same effect with LPS group (P =0.834).M PA did not affect the intracellular NF-κB p-p65 and pro-IL-1β protein levels but activated NLRP3 inflammasome.Ac-YVAD-cmk blocked the activation ofcaspase-1 and subsequently attenuated IL-1β secretion (181.00 ± 45.24 pg/ml in LPS + MPA + YVAD group vs.588.00 ± 41.99 pg/ml in LPS + MPA group,P =0.014).Conclusions:Taken together,MPA synergized with LPS to induce IL-1β release via the activation ofcaspase-1,rather than the enhanced production ofpro-IL-1β.These findings suggested that patients immunosuppressed with mycophenolate mofetil may have overly activated caspase-1 during infection,which might contribute to a more sensitive host defense response to invading germs.
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