期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 35, 期 -, 页码 61-69出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.intimp.2016.03.022
关键词
Hydrangenol; Nitric oxide; Nuclear factor-kappa B; Heme oxygenase-1; Nuclear factor erythroid 2-related factor 2
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF) from the Ministry of Education, Science and Technology of Korea [2015R1D1A1A01060538]
- National Research Foundation of Korea [2015R1D1A1A01060538] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
We previously demonstrated the anti-inflammatory effect of water extract of Hydrangea macrophylla in lipopolysaccharide (LPS)-stimulated macrophage cells. Here, we investigated whether hydrangenol, a bioactive component of H. macrophylla, attenuates the expression of nitric oxide (NO) and its associated gene, inducible NO synthase (iNOS), in LPS-stimulated BV2 microglial cells. Our data showed that low dosages of hydrangenol inhibited LPS-stimulated NO release and iNOS expression without any accompanying cytotoxicity. Hydrangenol also suppressed LPS-induced nuclear translocation of nuclear factor-kappa B (NF-kappa B) subunits, consequently inhibiting DNA-binding activity of NF-kappa B. Additionally, the NF-kappa B inhibitors, pyrrolidine dithiocarbamate (PDTC) and PS-1145, significantly attenuated LPS-induced iNOS expression, indicating that hydrangenol-induced NF-kappa B inhibition might be a key regulator of iNOS expression. Furthermore, our data showed that hydrangenol suppresses NO production by inducing heme oxygenase-1 (HO-1). The presence of cobalt protoporphyrin, a specific HO-1 inducer, potently suppressed LPS-induced NO production. Hydrangenol also promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequently increased its binding activity at the specific antioxidant response element sites. Additionally, transient knockdown of Nrf2 significantly downregulated hydrangenol-induced HO-1 expression, indicating that hydrangenol-induced Nrf2 is an upstream regulator of HO-1. Taken together, these data suggest that hydrangenol attenuates NO production and iNOS expression in LPS-stimulated BV2 microglial cells by inhibiting NF-kappa B activation and by stimulating the Nrf2-mediated HO-1 signaling pathway. Therefore, hydrangenol is a promising therapeutic agent for treatment of LPS-mediated inflammatory diseases. (C) 2016 Elsevier B.V. All rights reserved.
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