Docosahexaenoic acid and palmitic acid reciprocally modulate monocyte activation in part through endoplasmic reticulum stress.
Palmitic acid (C16:0) and TLR2 ligand induce, but docosahexaenoic acid (DHA) inhibits monocyte activation. C16:0 and TLR2 or TLR4 ligand induce certain ER stress markers; thus, we determined whether ER stress induced by these agonists is sufficient to induce monocyte activation, and whether the ER stress is inhibited by DHA which is known to inhibit C16:0- or ligand-induced TLR activation. Monocyte activation and ER stress were assessed by TLR/inflammasome-induced IL-1β production, and phosphorylation of IRE-1 and eIF2 and expression of CHOP, respectively in THP-1 cells. TLR2 ligand Pam3CSK4 induced phosphorylation of eIF2, but not phosphorylation of IRE-1 and CHOP expression. LPS also induced phosphorylation of both IRE-1 and eIF2 but not CHOP expression suggesting that TLR2 or TLR4 ligand, or C16:0 induces different ER stress responses. C16:0-, Pam3CSK4-, or LPS-induced IL-1β production was inhibited by 4-phenylbutyric acid, an inhibitor of ER stress suggesting that IL-1β production induced by these agonists is partly mediated through ER stress. Among two ER stress-inducing molecules, thapsigargin but not tunicamycin led to the expression of pro-IL-1β and secretion of IL-1β. Thus, not all types of ER stress are sufficient to induce inflammasome-mediated IL-1β secretion in monocytes. Although both C16:0 and thapsigargin-induced IL-1β secretion was inhibited by DHA, only C16:0-mediated ER stress was responsive to DHA. These findings suggest that the anti-inflammatory effects of DHA are at least in part mediated through modulating ER homeostasis and that the propensity of ER stress can be differentially modulated by the types of dietary fat we consume.
['Snodgrass|Ryan G|RG|', 'Huang|Shurong|S|', 'Namgaladze|Dmitry|D|', 'Jandali|Ola|O|', 'Shao|Tiffany|T|', 'Sama|Spandana|S|', 'Brüne|Bernhard|B|', 'Hwang|Daniel H|DH|']
D000894:Anti-Inflammatory Agents, Non-Steroidal D015415:Biomarkers D002460:Cell Line D004281:Docosahexaenoic Acids D059865:Endoplasmic Reticulum Stress D004791:Enzyme Inhibitors D056572:Histone Deacetylase Inhibitors D006801:Humans D056747:Immunomodulation D058847:Inflammasomes D053583:Interleukin-1beta D008024:Ligands D055666:Lipopeptides D008070:Lipopolysaccharides D009000:Monocytes D019308:Palmitic Acid D010654:Phenylbutyrates D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases D015398:Signal Transduction D019284:Thapsigargin D051195:Toll-Like Receptor 2 D051197:Toll-Like Receptor 4
Monocyte DHA ER stress Fatty acid Inflammasome Inflammation