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.
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