Glycyrrhizin derivative inhibits eotaxin 1 production via STAT6 in human lung fibroblasts.
We recently demonstrated that glycyrrhizin (GL) and its derivatives down-regulate TNFalpha- 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 (3beta-[(2-O-beta-D-glucopyranuronosyl-beta-D-glucopyranuronosyl)oxy]-olean-11,13(18)-dien-30-ol) showed marked inhibition of eotaxin 1 production with less cytotoxicity than 18beta-GL. To identify the molecular mechanism of this effect, we focused on the inhibition of the transcriptional factors NF-kappaB 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 18beta-GL and significantly inhibited by hetero-30-OH-GL. While IkappaBalpha degradation and translocation of NF-kappaB 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.
Matsui
Sachiko
S
International Department, Minophagen Pharmaceutical Co., Ltd., Japan.
Sonoda
Yoshiko
Y
Sekiya
Takashi
T
Aizu-Yokota
Eriko
E
Kasahara
Tadashi
T
D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000096:biosynthesis* / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000187:drug effects*; D019695:Glycyrrhizic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000502:physiology*
D054413:Chemokine CCL11; D016328:NF-kappa B; D012333:RNA, Messenger; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D019695:Glycyrrhizic Acid