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Title: Luteolin, a flavonoid, inhibits AP-1 activation by basophils

Abstract

Flavonoids including luteolin, apigenin, and fisetin are inhibitors of IL-4 synthesis and CD40 ligand expression by basophils. This study was done to search for compounds with greater inhibitory activity of IL-4 expression and to clarify the molecular mechanisms through which flavonoids inhibit their expression. Of the 37 flavonoids and related compounds examined, ayanin, luteolin, and apigenin were the strongest inhibitors of IL-4 production by purified basophils in response to anti-IgE antibody plus IL-3. Luteolin did not suppress Syk or Lyn phosphorylation in basophils, nor did suppress p54/46 SAPK/JNK, p38 MAPK, and p44/42 MAPK activation by a basophilic cell line, KU812 cells, stimulated with A23187 and PMA. However, luteolin did inhibit phosphorylation of c-Jun and DNA binding activity of AP-1 in nuclear lysates from stimulated KU812 cells. These results provide a fundamental structure of flavonoids for IL-4 inhibition and demonstrate a novel action of flavonoids that suppresses the activation of AP-1.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]; ; ;  [1]; ;  [2]; ;  [3];  [1];  [4]
  1. Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Medical School, Osaka 565-0871 (Japan)
  2. Kyoto Pharmaceutical University, Kyoto 607-8412 (Japan)
  3. Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871 (Japan)
  4. Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Medical School, Osaka 565-0871 (Japan). E-mail: ttanak@imed3.med.osaka-u.ac.jp
Publication Date:
OSTI Identifier:
20798770
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 340; Journal Issue: 1; Other Information: DOI: 10.1016/j.bbrc.2005.11.157; PII: S0006-291X(05)02705-1; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBODIES; BASOPHILS; BIOSYNTHESIS; DNA; FLAVONOIDS; INHIBITION; LIGANDS; LYMPHOKINES; PHOSPHORYLATION

Citation Formats

Hirano, Toru, Higa, Shinji, Arimitsu, Junsuke, Naka, Tetsuji, Ogata, Atsushi, Shima, Yoshihito, Fujimoto, Minoru, Yamadori, Tomoki, Ohkawara, Tomoharu, Kuwabara, Yusuke, Kawai, Mari, Matsuda, Hisashi, Yoshikawa, Masayuki, Maezaki, Naoyoshi, Tanaka, Tetsuaki, Kawase, Ichiro, and Tanaka, Toshio. Luteolin, a flavonoid, inhibits AP-1 activation by basophils. United States: N. p., 2006. Web. doi:10.1016/j.bbrc.2005.11.157.
Hirano, Toru, Higa, Shinji, Arimitsu, Junsuke, Naka, Tetsuji, Ogata, Atsushi, Shima, Yoshihito, Fujimoto, Minoru, Yamadori, Tomoki, Ohkawara, Tomoharu, Kuwabara, Yusuke, Kawai, Mari, Matsuda, Hisashi, Yoshikawa, Masayuki, Maezaki, Naoyoshi, Tanaka, Tetsuaki, Kawase, Ichiro, & Tanaka, Toshio. Luteolin, a flavonoid, inhibits AP-1 activation by basophils. United States. doi:10.1016/j.bbrc.2005.11.157.
Hirano, Toru, Higa, Shinji, Arimitsu, Junsuke, Naka, Tetsuji, Ogata, Atsushi, Shima, Yoshihito, Fujimoto, Minoru, Yamadori, Tomoki, Ohkawara, Tomoharu, Kuwabara, Yusuke, Kawai, Mari, Matsuda, Hisashi, Yoshikawa, Masayuki, Maezaki, Naoyoshi, Tanaka, Tetsuaki, Kawase, Ichiro, and Tanaka, Toshio. Fri . "Luteolin, a flavonoid, inhibits AP-1 activation by basophils". United States. doi:10.1016/j.bbrc.2005.11.157.
@article{osti_20798770,
title = {Luteolin, a flavonoid, inhibits AP-1 activation by basophils},
author = {Hirano, Toru and Higa, Shinji and Arimitsu, Junsuke and Naka, Tetsuji and Ogata, Atsushi and Shima, Yoshihito and Fujimoto, Minoru and Yamadori, Tomoki and Ohkawara, Tomoharu and Kuwabara, Yusuke and Kawai, Mari and Matsuda, Hisashi and Yoshikawa, Masayuki and Maezaki, Naoyoshi and Tanaka, Tetsuaki and Kawase, Ichiro and Tanaka, Toshio},
abstractNote = {Flavonoids including luteolin, apigenin, and fisetin are inhibitors of IL-4 synthesis and CD40 ligand expression by basophils. This study was done to search for compounds with greater inhibitory activity of IL-4 expression and to clarify the molecular mechanisms through which flavonoids inhibit their expression. Of the 37 flavonoids and related compounds examined, ayanin, luteolin, and apigenin were the strongest inhibitors of IL-4 production by purified basophils in response to anti-IgE antibody plus IL-3. Luteolin did not suppress Syk or Lyn phosphorylation in basophils, nor did suppress p54/46 SAPK/JNK, p38 MAPK, and p44/42 MAPK activation by a basophilic cell line, KU812 cells, stimulated with A23187 and PMA. However, luteolin did inhibit phosphorylation of c-Jun and DNA binding activity of AP-1 in nuclear lysates from stimulated KU812 cells. These results provide a fundamental structure of flavonoids for IL-4 inhibition and demonstrate a novel action of flavonoids that suppresses the activation of AP-1.},
doi = {10.1016/j.bbrc.2005.11.157},
journal = {Biochemical and Biophysical Research Communications},
number = 1,
volume = 340,
place = {United States},
year = {Fri Feb 03 00:00:00 EST 2006},
month = {Fri Feb 03 00:00:00 EST 2006}
}
  • Highlights: • SHQA increases PPARα/γ transactivation and inhibits MMP-2/-9 expression. • SHQA inhibits TNFα-induced AP-1 and MAPK signaling. • SHQA inhibits TNFα-induced p65 translocation and IκBα phosphorylation. • SHQA inhibits TNFα-induced AP-1 and NF-κB signaling via PPARα. - Abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors and expressed in various cell types in the skin, including keratinocytes, fibroblasts and infiltrating immune cells. Thus, their ligands are targets for the treatment of various skin disorders, such as photo-aging and chronological aging of skin. Intensive studies have revealed that PPARα/γ functions in photo-agingmore » and age-related inflammation by regulating matrix metalloproteinases (MMPs) via activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB). However, the detailed mechanism of PPARα/γ’s role in skin aging has not yet been elucidated. In this study, we confirmed that sargahydroquinoic acid (SHQA) as a PPARα/γ ligand significantly decreased Tumor Necrosis Factor-alpha (TNFα)-induced MMP-2/-9 expression by downregulating TNFα-induced transcription factors, subsequently reducing IκBα degradation and blocking NF-κB p65 nuclear translocation in HaCaT human epidermal keratinocyte cells. Treatment of cells with SHQA and GW6471 (PPARα antagonist) not bisphenol A diglycidyl ether (PPARγ antagonists), reversed the effect on TNFα-induced inflammatory signaling pathway activation. Taken together, our data suggest that SHQA inhibit TNFα-induced MMP-2/-9 expression and age-related inflammation by suppressing AP-1 and NF-κB pathway via PPARα.« less
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  • Research highlights: {yields} Kaempferol inhibits HIF-1 activity in hepatocarcinoma cells; {yields} Kaempferol causes cytoplasmic mislocalization of HIF-1{alpha} by impairing the MAPK pathway. {yields} Viability of hepatocarcinoma cells under hypoxia is reduced by kaempferol. -- Abstract: Hepatocellular carcinoma (HCC) is characterized by high mortality rates and resistance to conventional treatment. HCC tumors usually develop local hypoxia, which stimulates proliferation of cancer cells and renders them resilient to chemotherapy. Adaptation of tumor cells to the hypoxic conditions depends on the hypoxia-inducible factor 1 (HIF-1). Over-expression of its regulated HIF-1{alpha} subunit, an important target of anti-cancer therapy, is observed in many cancers includingmore » HCC and is associated with severity of tumor growth and poor patient prognosis. In this report we investigate the effect of the dietary flavonoid kaempferol on activity, expression levels and localization of HIF-1{alpha} as well as viability of human hepatoma (Huh7) cancer cells. Treatment of Huh7 cells with kaempferol under hypoxic conditions (1% oxygen) effectively inhibited HIF-1 activity in a dose-dependent manner (IC{sub 50} = 5.16 {mu}M). The mechanism of this inhibition did not involve suppression of HIF-1{alpha} protein levels but rather its mislocalization into the cytoplasm due to inactivation of p44/42 MAPK by kaempferol (IC{sub 50} = 4.75 {mu}M). Exposure of Huh7 cells to 10 {mu}{Mu} kaempferol caused significant reduction of their viability, which was remarkably more evident under hypoxic conditions. In conclusion, kaempferol, a non-toxic natural food component, inhibits both MAPK and HIF-1 activity at physiologically relevant concentrations (5-10 {mu}M) and suppresses hepatocarcinoma cell survival more efficiently under hypoxia. It has, therefore, potential as a therapeutic or chemopreventive anti-HCC agent.« less
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