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2017 ; 12
(5
): e0176793
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Palmitic acid is a toll-like receptor 4 ligand that induces human dendritic cell
secretion of IL-1?
#MMPMID28463985
Nicholas DA
; Zhang K
; Hung C
; Glasgow S
; Aruni AW
; Unternaehrer J
; Payne KJ
; Langridge WHR
; De Leon M
PLoS One
2017[]; 12
(5
): e0176793
PMID28463985
show ga
Palmitic acid (PA) and other saturated fatty acids are known to stimulate
pro-inflammatory responses in human immune cells via Toll-like receptor 4 (TLR4).
However, the molecular mechanism responsible for fatty acid stimulation of TLR4
remains unknown. Here, we demonstrate that PA functions as a ligand for TLR4 on
human monocyte derived dendritic cells (MoDCs). Hydrophobicity protein modeling
indicated PA can associate with the hydrophobic binding pocket of TLR4 adaptor
protein MD-2. Isothermal titration calorimetry quantified heat absorption that
occurred during PA titration into TLR4/MD2, indicating that PA binds to TLR4/MD2.
Treatment of human MoDCs with PA resulted in endocytosis of TLR4, further
supporting the function of PA as a TLR4 agonist. In addition, PA stimulated DC
maturation and activation based on the upregulation of DC costimulatory factors
CD86 and CD83. Further experiments showed that PA induced TLR4 dependent
secretion of the pro-inflammatory cytokine IL-1?. Lastly, our experimental data
show that PA stimulation of NF-?B canonical pathway activation is regulated by
TLR4 signaling and that reactive oxygen species may be important in upregulating
this pro-inflammatory response. Our experiments demonstrate for the first time
that PA activation of TLR4 occurs in response to direct molecular interactions
between PA and MD-2. In summary, our findings suggest a likely molecular
mechanism for PA induction of pro-inflammatory immune responses in human
dendritic cells expressing TLR4.