Intestinal anti-inflammatory activity of luteolin: Role of the aglycone in NF-κB inactivation in macrophages co-cultured with intestinal epithelial cells

Authors

  • Yosuke Nishitani,

    1. Organization of Advanced Science and Technology, Kobe University, Nada-ku, Kobe 657-8501, Japan
    Search for more papers by this author
  • Koji Yamamoto,

    1. Gastroenterology Division, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japan
    Search for more papers by this author
  • Masaru Yoshida,

    1. Gastroenterology Division, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japan
    2. The Integrated Center for Mass Spectrometry, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japan
    Search for more papers by this author
  • Takeshi Azuma,

    1. Gastroenterology Division, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Chuo-ku, Kobe 650-0017, Japan
    Search for more papers by this author
  • Kazuki Kanazawa,

    1. Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Nada-ku, Kobe 657-8501, Japan
    Search for more papers by this author
  • Takashi Hashimoto,

    1. Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Nada-ku, Kobe 657-8501, Japan
    Search for more papers by this author
  • Masashi Mizuno

    Corresponding author
    1. Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Nada-ku, Kobe 657-8501, Japan
    • Address for correspondence to: Masashi Mizuno, PhD, Rokkodai-cho 1-1, Nada-ku, Kobe 657-8501, Hyogo, Japan. Tel.: 81-78-803-5835; Fax: +81-78-803-5835; E-mail: mizuno@kobe-u.ac.jp

    Search for more papers by this author

Abstract

The flavonoid luteolin is reported to exert anti-inflammatory properties. In this study, we investigated whether luteolin inhibits gut inflammation, using in vivo and in vitro inflammation models. In a dextran sulfate sodium (DSS)-induced colitis mouse model, luteolin (20 and 50 mg/kg) significantly ameliorated shortening of colon length and histological score. Immunohistochemical analysis showed that luteolin also significantly inhibited infiltration of macrophages and interferon (IFN)-γ-producing CD4+ T cells into the colonic mucosa. Treatment with luteolin also improved IFN-γ mRNA expression in the colon. At the cellular level, a co-culture consisting of intestinal epithelial Caco-2 and macrophage RAW264.7 cells, stimulated with lipopolysaccharide, the addition of luteolin (100 μM) suppressed interleukin (IL)-8 mRNA expression in Caco-2 cells without epithelial monolayer disruption. Expression of tumor necrosis factor (TNF)-α protein and proinflammatory cytokines mRNA (TNF-α, IL-6, and IL-1β) in RAW264.7 cells were also suppressed. HPLC analysis and subsequent cellular assay revealed that aglycone of luteolin was present in the basolateral supernatant of this system at a sufficient concentration to suppress TNF-α production and nuclear factor (NF)-κB activation of RAW264.7 cells. These results suggest that the luteolin aglycones released from the Caco-2 epithelium inhibits NF-κB nuclear translocation in RAW264.7 cells, followed by reduction of TNF-α mRNA expression, which results in downregulation of IL-8 mRNA expression in Caco-2 cells. The mechanism by which aglycone inhibits inflammation is important for understanding the roles of luteolin in diet. © 2013 BioFactors 39(5):522–533, 2013

Ancillary