Regiospecific methylation of a dietary flavonoid scaffold selectively enhances IL-1β production following Toll-like receptor 2 stimulation in THP-1 monocytes

TY - JOUR

T1 - Regiospecific methylation of a dietary flavonoid scaffold selectively enhances IL-1β production following Toll-like receptor 2 stimulation in THP-1 monocytes

AU - Lim, Eng-Kiat

AU - Mitchell, Paul J

AU - Brown, Najmeeyah

AU - Drummond, Rebecca A

AU - Brown, Gordon D

AU - Kaye, Paul M

AU - Bowles, Dianna J

N1 - Joint corresponding author

PY - 2013/7/19

Y1 - 2013/7/19

N2 - It is now recognized that innate immunity to intestinal microflora plays a significant role in mediating immune health, and modulation of microbial sensing may underpin the impact of plant natural products in the diet or when used as nutraceuticals. In this context, we have examined five classes of plant-derived flavonoids (flavonols, flavones, flavanones, catechins, and cyanidin) for their ability to regulate cytokine release induced by the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We found that the flavonols selectively co-stimulated IL-1β secretion but had no impact on the secretion of IL-6. Importantly, this costimulation of TLR2-induced cytokine secretion was dependent on regiospecific methylation of the flavonol scaffold with a rank order of quercetin-3,4'-dimethylether > quercetin-3-methylether > casticin. The mechanism underpinning this costimulation did not involve enhanced inflammasome activation. In contrast, the methylated flavonols enhanced IL-1β gene expression through transcriptional regulation, involving mechanisms that operate downstream of the initial NF-κB and STAT1 activation events. These studies demonstrate an exquisite level of control of scaffold bioactivity by regiospecific methylation, with important implications for understanding how natural products affect innate immunity and for their development as novel immunomodulators for clinical use.

AB - It is now recognized that innate immunity to intestinal microflora plays a significant role in mediating immune health, and modulation of microbial sensing may underpin the impact of plant natural products in the diet or when used as nutraceuticals. In this context, we have examined five classes of plant-derived flavonoids (flavonols, flavones, flavanones, catechins, and cyanidin) for their ability to regulate cytokine release induced by the Toll-like receptor 2 (TLR2) agonist Pam3CSK4. We found that the flavonols selectively co-stimulated IL-1β secretion but had no impact on the secretion of IL-6. Importantly, this costimulation of TLR2-induced cytokine secretion was dependent on regiospecific methylation of the flavonol scaffold with a rank order of quercetin-3,4'-dimethylether > quercetin-3-methylether > casticin. The mechanism underpinning this costimulation did not involve enhanced inflammasome activation. In contrast, the methylated flavonols enhanced IL-1β gene expression through transcriptional regulation, involving mechanisms that operate downstream of the initial NF-κB and STAT1 activation events. These studies demonstrate an exquisite level of control of scaffold bioactivity by regiospecific methylation, with important implications for understanding how natural products affect innate immunity and for their development as novel immunomodulators for clinical use.

U2 - 10.1074/jbc.M113.453514

DO - 10.1074/jbc.M113.453514

M3 - Article

C2 - 23760261

SN - 0021-9258

VL - 288

SP - 21126

EP - 21135

JO - The Journal of biological chemistry

JF - The Journal of biological chemistry

IS - 29

ER -