title: Docosahexaenoic acid and palmitic acid reciprocally modulate monocyte activation in part through endoplasmic reticulum stress.
abstract: 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.
authors.affiliation: U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616; Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Snodgrass
authors.affiliation: U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616.
authors.forename: Shurong
authors.initials: S
authors.lastname: Huang
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Namgaladze
authors.affiliation: U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616.
authors.forename: Ola
authors.initials: O
authors.lastname: Jandali
authors.affiliation: U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Shao
authors.affiliation: U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616.
authors.forename: Spandana
authors.initials: S
authors.lastname: Sama
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.affiliation: U.S. Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA 95616. Electronic address: daniel.hwang@ars.usda.gov.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hwang
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D004281:Docosahexaenoic Acids / Q000378:metabolism* / Q000627:therapeutic use; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D056747:Immunomodulation; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000819:agonists / Q000378:metabolism; D008024:Ligands; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D019308:Palmitic Acid / Q000009:adverse effects / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D008024:Ligands; D055666:Lipopeptides; D008070:Lipopolysaccharides; C508075:Pam(3)CSK(4) peptide; D010654:Phenylbutyrates; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D004281:Docosahexaenoic Acids; D019308:Palmitic Acid; D019284:Thapsigargin; C075773:4-phenylbutyric acid; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: DHA; ER stress; Fatty acid; Inflammasome; Inflammation; Monocyte