2',4',6'-tris(methoxymethoxy) chalcone protects against trinitrobenzene sulfonic acid-induced colitis and blocks tumor necrosis factor-alpha-induced intestinal epithelial inflammation via heme oxygenase 1-dependent and independent pathways.
2',4',6'-Tris(methoxymethoxy) chalcone (TMMC), a synthesized chalcone derivative, displays potent antiproliferative and anti-inflammatory effects in rat hepatic stellate cells and murine macrophages, respectively. Here we tested the hypothesis that TMMC could ameliorate diseases characterized by mucosal inflammation. Treatment of mice with TMMC significantly protected against trinitrobenzene sulfonic acid (TNBS)-induced colitis, as assessed by reductions in the weight loss, colonic damage and mucosal ulceration that together characterize this symptom. Moreover, TMMC suppressed the expression of intercellular adhesion molecule-1, interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in the mice treated with TNBS. Pretreatment of human intestinal epithelial HT-29 cells with TMMC also significantly inhibited the IL-8 and extracellular matrix metalloproteinase-7 levels induced by TNF-alpha. TMMC induced the expression of heme oxygenase 1 (HO-1) in HT-29 cells. TMMC increased extracellular signal-regulated kinase1/2 and p38 kinase phosphorylation levels, which led to the nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and consequently to HO-1 expression. TMMC inhibited TNF-alpha-induced nuclear factor kappaB (NF-kappaB) activation directly and indirectly. Interestingly, the latter is mediated by HO-1, which presumably blocks the TNF-alpha-induced nuclear translocation of NF-kappaB p65 without affecting I-kappaBalpha degradation. Moreover, we found that the different products of HO-1, carbon monoxide and bilirubin, exerted anti-inflammatory effects that were additive or synergistic in HT-29 cells stimulated with TNF-alpha. Thus, TMMC might serve to protect against intestinal inflammatory diseases.
Lee
Sung Hee
SH
College of Pharmacy, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea.
Sohn
Dong Hwan
DH
Jin
Xing Yu
XY
Kim
Sang Wook
SW
Choi
Suck Chei
SC
Seo
Geom Seog
GS
D000818:Animals; D002460:Cell Line; D002599:Chalcone / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced* / Q000517:prevention & control*; D004848:Epithelium / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007249:Inflammation / Q000517:prevention & control*; D007422:Intestines / Q000473:pathology; D051379:Mice; D009092:Mucous Membrane / Q000473:pathology; D020011:Protective Agents; D015398:Signal Transduction / Q000187:drug effects; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000037:antagonists & inhibitors
D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D002599:Chalcone; D014302:Trinitrobenzenesulfonic Acid; D051547:Heme Oxygenase-1