Butein blocks tumor necrosis factor alpha-induced interleukin 8 and matrix metalloproteinase 7 production by inhibiting p38 kinase and osteopontin mediated signaling events in HT-29 cells.
In this study, we evaluated whether butein can inhibit the effects of tumor necrosis factor alpha (TNF-alpha), an inflammatory mediator, in intestinal epithelial HT-29 cells. Butein significantly inhibited TNF-alpha-induced interleukin 8 (IL-8) secretion and mRNA expression. Moreover, butein suppressed the expression of matrix metalloproteinase 7 (MMP-7) mRNA and extracellular pro-MMP-7 secretion. The signal transduction study revealed that butein significantly attenuates p38 phosphorylation and inhibits osteopontin (OPN) mediated inhibitory factor kappaBalpha (I-kappaBalpha) phosphorylation in TNF-alpha-stimulated HT-29 cells. Using specific kinase inhibitors, we also found that blocking the p38 pathway is critical for, and blocking of OPN-mediated I-kappaBalpha phosphorylation pathway is at least for, the inhibitory effect by butein on TNF-alpha-induced IL-8 and MMP-7 expression. Furthermore, using an MMP inhibitor, we showed that IL-8 lies upstream of MMP-7 in the TNF-alpha-induced signaling process in HT-29 cells. Collectively, these results suggest that butein may be an effective agent for the treatment of intestinal inflammation.
Lee
Sung Hee
SH
College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Seo
Geom Seog
GS
Jin
Xing Yu
XY
Ko
Geonil
G
Sohn
Dong Hwan
DH
D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D004791:Enzyme Inhibitors; D019073:HT29 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007202:Indicators and Reagents; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis*; D061965:Matrix Metalloproteinase Inhibitors; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D047188:Chalcones; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D016209:Interleukin-8; D061965:Matrix Metalloproteinase Inhibitors; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D053495:Osteopontin; C040918:butein; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D020783:Matrix Metalloproteinase 7