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.