title: Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways.
abstract: Toll-like receptor 4 (TLR4) and TLR2 were shown to be activated by saturated fatty acids (SFAs) but inhibited by docosahexaenoic acid (DHA). However, one report suggested that SFA-induced TLR activation in cell culture systems is due to contaminants in BSA used for solubilizing fatty acids. This report raised doubt about proinflammatory effects of SFAs. Our studies herein demonstrate that sodium palmitate (C16:0) or laurate (C12:0) without BSA solubilization induced phosphorylation of inhibitor of nuclear factor-κB α, c-Jun N-terminal kinase (JNK), p44/42 mitogen-activated-kinase (ERK), and nuclear factor-κB subunit p65, and TLR target gene expression in THP1 monocytes or RAW264.7 macrophages, respectively, when cultured in low FBS (0.25%) medium. C12:0 induced NFκB activation through TLR2 dimerized with TLR1 or TLR6, and through TLR4. Because BSA was not used in these experiments, contaminants in BSA have no relevance. Unlike in suspension cells (THP-1), BSA-solubilized C16:0 instead of sodium C16:0 is required to induce TLR target gene expression in adherent cells (RAW264.7). C16:0-BSA transactivated TLR2 dimerized with TLR1 or TLR6 and through TLR4 as seen with C12:0. These results and additional studies with the LPS sequester polymixin B and in MyD88(-/-) macrophages indicated that SFA-induced activation of TLR2 or TLR4 is a fatty acid-specific effect, but not due to contaminants in BSA or fatty acid preparations.
authors: Western Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Department of Anatomy, Physiology and Cell Biology, University of California, Davis, CA, USA.
authors: Shurong
authors: S
authors: Huang
authors: Jennifer M
authors: JM
authors: Rutkowsky
authors: Ryan G
authors: RG
authors: Snodgrass
authors: Kikumi D
authors: KD
authors: Ono-Moore
authors: Dina A
authors: DA
authors: Schneider
authors: John W
authors: JW
authors: Newman
authors: Sean H
authors: SH
authors: Adams
authors: Daniel H
authors: DH
authors: Hwang
mesh_terms: D000818:Animals; D002460:Cell Line; D005227:Fatty Acids / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors