Research Paper
Subject Categories: Immunopharmacology and inflammation
British Journal of Pharmacology (2007) 150, 209–219. doi:10.1038/sj.bjp.0706972; published online 11 December 2006
Ergosterol peroxide from an edible mushroom suppresses inflammatory responses in RAW264.7 macrophages and growth of HT29 colon adenocarcinoma cells
M Kobori1, M Yoshida1, M Ohnishi-Kameyama1 and H Shinmoto1
1National Food Research Institute, Tsukuba, Ibaraki, Japan
Correspondence: Dr M Kobori, National Food Research Institute, 2-1-12 Kannondai, Tsukuba, Ibaraki 305-8642, Japan. E-mail: kobori@affrc.go.jp
Received 14 August 2006; Revised 2 October 2006; Accepted 18 October 2006; Published online 11 December 2006.
Abstract
Background and purpose:
5
,8-Epidioxy-22E-ergosta-6, 22-dien-3
-ol (ergosterol peroxide) is a major antitumour sterol produced by edible or medicinal mushrooms. However, its molecular mechanism of action has yet to be determined. Here, we examine the anticancer and anti-inflammatory effects of ergosterol peroxide.
Experimental approach:
After treating RAW264.7 macrophages with LPS and purified ergosterol peroxide or ergosterol, we determined LPS-induced inflammatory cytokines, nuclear DNA binding activity of transcription factors and phosphorylation of MAP kinases (MAPKs). HT29 colorectal adenocarcinoma cells were treated with ergosterol peroxide for 5 days. To investigate the antitumour properties of ergosterol peroxide, we performed DNA microarray and RT-PCR analyses and determined the reactive oxygen species (ROS) in HT29 cells.
Key results:
Ergosterol peroxide suppressed LPS-induced TNF- secretion and IL-1
/
expression in RAW264.7 cells. Ergosterol peroxide and ergosterol suppressed LPS-induced DNA binding activity of NF-
B and C/EBP, and inhibited the phosphorylation of p38, JNK and ERK MAPKs. Ergosterol peroxide down-regulated the expression of low-density lipoprotein receptor (LDLR) regulated by C/EBP, and HMG-CoA reductase (HMGCR) in RAW264.7 cells. In addition, ergosterol peroxide showed cytostatic effects on HT29 cells and increased intracellular ROS. Furthermore, ergosterol peroxide induced the expression of oxidative stress-inducible genes, and the cyclin-dependent kinase inhibitor CDKN1A, and suppressed STAT1 and interferon-inducible genes.
Conclusion and Implication:
Our results suggest that ergosterol peroxide and ergosterol suppress LPS-induced inflammatory responses through inhibition of NF-B and C/EBP transcriptional activity, and phosphorylation of MAPKs. Moreover, ergosterol peroxide appears to suppress cell growth and STAT1 mediated inflammatory responses by altering the redox state in HT29 cells.
Keywords:
ergosterol peroxide, inflammation, RAW264.7 macrophage-like cells, NF-
B, C/EBP, HT29 human colorectal adenocarcinoma cells, reactive oxigen species (ROS)
Abbreviations:
AKR1C1, aldo-keto reductase family 1 member C1; CDKN1A, cyclin-dependent kinase inhibitor p21(WAF1/Cip1); ergosterol peroxide, 5,8-epidioxy-22E-ergosta-6,22-dien-3-ol; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMGCR, 3-hydroxy-3-methylglutamyl-coenzyme A reductase; HMGCS, 3-hydroxy-3-methylglutamyl-coenzyme A synthase; IL-1, interleukin-1; LDLR, low-density lipoprotein receptor; LPS, lipopolysaccharide; NF-B, nuclear factor-B; ROS, reactive oxygen species; RT–PCR, real-time reverse transcription–polymerase chain reaction; S. aspratus, Sarcodon aspratus (Berk.) S. Ito; SREBP, sterol regulatory element binding protein; TNF-, tumour necrosis factor-; TPA, phorbol-12-myristate 13-acetate; 9,11-dehydroerogosterol peroxide, 5,8-epidioxy-22E-ergosta-6, 9(11), 22-trien-3-ol
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