title: Inhibitory effect of 10-hydroxydecanoic acid on lipopolysaccharide-induced nitric oxide production via translational downregulation of interferon regulatory factor-1 in RAW264 murine macrophages.
abstract: Toll-like receptors (TLRs) play a critical role in innate immunity by recognizing pathogen-associated molecular patterns. Various environmental materials including lipids may affect TLR signaling and modulate innate immune responses. We previously reported that 10-hydroxy-trans-2-decenoic acid (10H2DA) inhibits lipopolysaccharide (LPS)-induced interleukin (IL)-6 and nitric oxide (NO) production via inhibiting NF-κB activation. In this study, we investigated the effect of 10-hydroxydecanoic acid (10HDA), a saturated fatty acid of 10H2DA, on LPS-induced cytokines/chemokines and NO production. 10HDA inhibited LPS-induced NO production, but not tumor necrosis factor-α or IL-6 production. LPS-induced activation of interferon (IFN)-stimulated response element, but not NF-κB, was inhibited by 10HDA. Phosphorylation of STAT1 and STAT2 was not affected, but IFN-regulatory factor (IRF)-1 production was significantly reduced by 10HDA. The LPS-induced increase of IRF-1 mRNA, however, was not affected by 10HDA. We found that IRF-1 mRNA level in the polysomal fraction was significantly decreased by 10HDA. Further, LPS-induced phosphorylation of Akt and 4E-BP1, which control mRNA translation, was markedly decreased. These results suggest that 10HDA inhibited LPS-induced NO production through inhibiting IRF-1 translation. These findings elucidate a novel mechanism for anti-inflammatory activity of medium-chain fatty acid 10HDA.
authors.affiliation: Department of Biopharmaceutical Sciences, Laboratory of Microbiology, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Takahashi
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Shunji
authors.initials: S
authors.lastname: Tokoro
authors.forename: Paol
authors.initials: P
authors.lastname: Neri
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003652:Decanoic Acids; D039642:Eukaryotic Initiation Factors; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000621793:10-hydroxydecanoic acid; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016207:Cytokines; D003652:Decanoic Acids; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D005229:Fatty Acids, Monounsaturated; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D009569:Nitric Oxide; C055543:10-hydroxy-2-decenoic acid; D052247:Nitric Oxide Synthase Type II; D051057:Proto-Oncogene Proteins c-akt