Reduced scytonemin isolated from Nostoc commune suppresses LPS/IFNγ-induced NO production in murine macrophage RAW264 cells by inducing hemeoxygenase-1 expression via the Nrf2/ARE pathway.

Reduced scytonemin (R-scy) and scytonemin (Scy) isolated from Nostoc commune exhibit anti-tumor and ultraviolet-absorbing properties. In this study, we examined the effects of R-scy and Scy on the induction of nitric oxide (NO) production by lipopolysaccharide (LPS) and interferon-γ (IFNγ) in murine macrophage RAW264 cells. While both R-scy and Scy suppressed LPS/IFNγ-induced NO production, R-scy exhibited a stronger inhibitory effect compared with Scy. To further elucidate the mechanisms underlying the anti-inflammatory effects of R-scy, we examined the changes in the intracellular signaling cascade after LPS/IFNγ stimulation in cells. In addition to the attenuation of LPS/IFNγ-induced upregulation of the inducible isoform of NO synthase, R-scy decreased the activity of nuclear factor-κB, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinases (MAPKs) after LPS/IFNγ stimulation. R-scy treatment increased heme oxygenase-1 (HO-1) expression by increasing the intracellular levels of reactive oxygen species and thereby activating nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element signaling. The induction of HO-1 by R-scy was inhibited by pretreatment with an antioxidant, N-acetyl-cysteine (NAC), as well as SB203580 and LY294002, inhibitors for p38 MAPK and PI3K/Akt, respectively. Our findings suggest that the anti-inflammatory effects of R-scy could involve both the ROS/PI3K/Akt and the p38 MAPK/Nrf2 signaling pathways.
AuthorsTomohiro Itoh, Mamoru Koketsu, Naoto Yokota, Shota Touho, Masashi Ando, Yasuyuki Tsukamasa
JournalFood and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 69 Pg. 330-8 (Jul 2014) ISSN: 1873-6351 [Electronic] England
PMID24795232 (Publication Type: Journal Article)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Indoles
  • Keap1 protein, mouse
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Phenols
  • Reactive Oxygen Species
  • scytonemin
  • Nitric Oxide
  • Interferon-gamma
  • Heme Oxygenase-1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Adaptor Proteins, Signal Transducing (metabolism)
  • Animals
  • Antioxidant Response Elements (drug effects)
  • Cell Line (drug effects)
  • Cytoskeletal Proteins (metabolism)
  • Heme Oxygenase-1 (metabolism)
  • Indoles (isolation & purification, pharmacology)
  • Interferon-gamma (metabolism, pharmacology)
  • Lipopolysaccharides (pharmacology)
  • Macrophages (drug effects, metabolism)
  • Mice
  • NF-E2-Related Factor 2 (metabolism)
  • Nitric Oxide (metabolism)
  • Nostoc commune (chemistry)
  • Phenols (isolation & purification, pharmacology)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Reactive Oxygen Species (metabolism)
  • Signal Transduction (drug effects)

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