TY - JOUR
T1 - Glycyrrhizin derivative inhibits eotaxin 1 production via STAT6 in human lung fibroblasts
AU - Matsui, Sachiko
AU - Sonoda, Yoshiko
AU - Sekiya, Takashi
AU - Aizu-Yokota, Eriko
AU - Kasahara, Tadashi
N1 - Funding Information:
We thank Dr. Toshitsugu Sato and Dr. Hiroatsu Matsumoto for helpful discussions, and Ms. Kayoko Tani for her skillful assistance. We also thank Prof. Koichi Hirai and Prof. Kouji Matsushima for the construct of eotaxin 1 promoter. This study was supported partly by a Grant-in-Aid (16390024) from MEXT, Japan.
PY - 2006/3
Y1 - 2006/3
N2 - We recently demonstrated that glycyrrhizin (GL) and its derivatives down-regulate TNFα- and IL-4-induced eotaxin 1 production by the human fetal lung fibroblast line HFL-1 at protein or mRNA levels. In particular, the GL derivative hetero-30-OH-GL (3β-[(2-O-β-d-glucopyranuronosyl-β- d-glucopyranuronosyl)oxy]-olean-11,13(18)-dien-30-ol) showed marked inhibition of eotaxin 1 production with less cytotoxicity than 18β-GL. To identify the molecular mechanism of this effect, we focused on the inhibition of the transcriptional factors NF-κB and signal transducer and activator of transcription 6 (STAT6), which regulate eotaxin 1 gene activation. STAT6 phosphorylation and translocation of phospho-STAT6 from cytosol to nuclei were slightly inhibited by 18β-GL and significantly inhibited by hetero-30-OH-GL. While IκBα degradation and translocation of NF-κB p65 to nuclei were not significantly affected by either compound, the stability of eotaxin-1 mRNA was decreased with hetero-30-OH-GL. In addition, eotaxin 1 promoter activity was markedly inhibited by hetero-30-OH-GL. Electrophoretic mobility shift assay (EMSA) confirmed these results. Thus, hetero-30-OH-GL significantly inhibited eotaxin 1 expression by the selective inhibition of IL-4 signal transduction as well as by enhanced mRNA degradation.
AB - We recently demonstrated that glycyrrhizin (GL) and its derivatives down-regulate TNFα- and IL-4-induced eotaxin 1 production by the human fetal lung fibroblast line HFL-1 at protein or mRNA levels. In particular, the GL derivative hetero-30-OH-GL (3β-[(2-O-β-d-glucopyranuronosyl-β- d-glucopyranuronosyl)oxy]-olean-11,13(18)-dien-30-ol) showed marked inhibition of eotaxin 1 production with less cytotoxicity than 18β-GL. To identify the molecular mechanism of this effect, we focused on the inhibition of the transcriptional factors NF-κB and signal transducer and activator of transcription 6 (STAT6), which regulate eotaxin 1 gene activation. STAT6 phosphorylation and translocation of phospho-STAT6 from cytosol to nuclei were slightly inhibited by 18β-GL and significantly inhibited by hetero-30-OH-GL. While IκBα degradation and translocation of NF-κB p65 to nuclei were not significantly affected by either compound, the stability of eotaxin-1 mRNA was decreased with hetero-30-OH-GL. In addition, eotaxin 1 promoter activity was markedly inhibited by hetero-30-OH-GL. Electrophoretic mobility shift assay (EMSA) confirmed these results. Thus, hetero-30-OH-GL significantly inhibited eotaxin 1 expression by the selective inhibition of IL-4 signal transduction as well as by enhanced mRNA degradation.
KW - Eotaxin 1
KW - Glycyrrhizin derivatives
KW - Human lung fibroblast
KW - Nuclear factor-kappa B
KW - Signal transducer and activator of transcription 6
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U2 - 10.1016/j.intimp.2005.08.025
DO - 10.1016/j.intimp.2005.08.025
M3 - Article
C2 - 16428072
AN - SCOPUS:31044450232
VL - 6
SP - 369
EP - 375
JO - International Immunopharmacology
JF - International Immunopharmacology
SN - 1567-5769
IS - 3
ER -