calcimycin and fisetin

Interleukin-31 (IL-31) is a recently discovered cytokine that is tightly linked to the pathogenesis of pruritus seen in atopic dermatitis. Flavonoids, like fisetin, are naturally occurring molecules with antioxidant, cytoprotective, and anti-inflammatory actions.. the present study sought to investigate whether fisetin modulates IL-31 and histamine release in human mast cells (HMC-1).. HMC-1 cells were pretreated with fisetin at various doses and stimulated with phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PI) for different time intervals. We evaluated IL-31 production and histamine release and signaling mechanism of the action of fisetin on IL-31 production. We also investigated the effects of fisetin on scratching behaviors in mice.. Fisetin decreased PI-stimulated mRNA expression and production of IL-31 in HMC-1 cells. Fisetin inhibited PI-induced phosphorylation of mitogen-activated protein kinases that further suppressed nuclear factor (NF-κB) activation and translocation to the nucleus through the inhibition of IκB-α phosphorylation. Fisetin also prevented mast cell release of histamine in HMC-1 cells. Mice in-vivo studies show that fisetin reduced scratching behaviors in mice.. These pharmacological actions of fisetin provide new suggestions that fisetin can be of potential use for the treatment of pruritus that cannot be treated with histamine receptor blockers alone.

Topics: Animals; Calcimycin; Cell Line; Flavonoids; Flavonols; Histamine Release; Humans; Interleukins; MAP Kinase Signaling System; Mast Cells; Mice; Mice, Inbred ICR; Pruritus; RNA, Messenger; Signal Transduction; Tetradecanoylphorbol Acetate

We have previously shown that flavonoids such as luteolin, apigenin and fisetin inhibit interleukin 4 and interleukin 13 production. In this study, we investigated whether luteolin can suppress CD40 ligand expression by basophils.. A human basophilic cell line, KU812, was stimulated with A23187 and phorbol myristate acetate (PMA) with or without various concentrations of luteolin or other flavonoids for 12 h, and CD40 ligand expression was analyzed by FACS. The effect of luteolin on CD40 ligand mRNA expression was studied by semiquantitative reverse transcription PCR analysis. In addition, CD40 ligand expression was also measured in purified basophils that had been stimulated for 12 h with A23187 plus PMA with or without various concentrations of luteolin.. CD40 ligand expression by KU812 cells was enhanced noticeably in response to A23187 and even more strikingly augmented by A23187 plus PMA. The expression was significantly suppressed by 10 or 30 microM of luteolin, whereas myricetin failed to inhibit. Reverse transcription PCR analyses demonstrated that luteolin inhibited CD40 ligand mRNA expression by stimulated KU812 cells. Of the six flavonoids examined, luteolin, apigenin, fisetin and quercetin at 30 microM showed a significant inhibitory effect on CD40 ligand expression. The incubation of purified basophils with A23187 plus PMA significantly enhanced CD40 ligand expression, and the presence of luteolin again had an inhibitory effect.. Luteolin inhibits CD40 ligand expression by activated basophils.

Topics: Apigenin; Basophils; Calcimycin; CD40 Ligand; Cell Line; Flavonoids; Flavonols; Humans; Interleukin-4; Luteolin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tetradecanoylphorbol Acetate

We have shown previously that treatment of WB rat liver epithelial cells with the Ca2+ ionophore A23187 provokes a rapid increase in protein-tyrosine phosphorylation that faithfully reproduces the Ca(2+)-dependent response seen with angiotensin II. In the presence of the tyrosine phosphatase inhibitor o-vanadate (2.0-200 microM), the tyrosine phosphorylation response to A23187 was increased > 10-fold in magnitude. This synergistic effect of A23187 and vanadate is clearly distinct from the combined effect of angiotensin II and vanadate, which was merely additive. Chelation of either extracellular or intracellular Ca2+ abolished the synergistic response to ionophore and vanadate, indicating its Ca2+ dependence. That divergent pathways were involved in the angiotensin II and the A23187/vanadate responses was shown definitely by studies of GN4 cells, a transformed line derived from WB cells by carcinogen treatment. GN4 cells are 2-3-fold more responsive than WB cells to angiotensin II-dependent tyrosine kinase activation, yet they completely lacked the synergistic tyrosine phosphorylation response to A23187/vanadate. To test the role of arachidonic acid metabolites in the A23187/vanadate response, cells were pretreated with either indomethacin or nordihydroguaiaretic acid (NDGA). Neither compound was inhibitory, but surprisingly, NDGA plus vanadate closely mimicked the A23187/vanadate response in WB cells and, like A23187/vanadate, was ineffective in GN4 cells. NDGA contains catechol nuclei (i.e., aromatic 1,2-diols) and therein resembles the flavonoid anti-oxidant quercetin, another compound found to increase tyrosine phosphorylation synergistically with vanadate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcysteine; Angiotensin II; Animals; Calcimycin; Cell Line; Cell Line, Transformed; Drug Synergism; Egtazic Acid; Enzyme Activation; Flavonoids; Flavonols; Indomethacin; Liver; Masoprocol; Phosphorylation; Phosphotyrosine; Protein-Tyrosine Kinases; Quercetin; Rats; Tyrosine; Vanadates