Schaefer Katherine L, Denevich Svetlana, Ma Chen, Cooley Shane R, Nakajima Atsushi, Wada Koichiro, Schlezinger Jennifer, Sherr David, Saubermann Lawrence J
Section of Gastroenterology, Boston University Medical Center, Boston, Massachusetts 02118, USA.
Inflamm Bowel Dis. 2005 Mar;11(3):244-52. doi: 10.1097/01.mib.0000160770.94199.9b.
Crohn's disease is associated with an excessive T helper (TH) type 1 inflammatory immune response. Reducing the influx of disease-associated CD4+ TH1 cells into the inflamed intestine is likely to be beneficial in preventing a disease flare-up and even possibly in reducing the effect of acute disease. Thiazolidenedione (TZD) ligands, which activate peroxisome proliferator-activated receptor-gamma (PPARgamma), have been shown to reduce TH1 inflammation in murine models of colitis, primarily in a preventative fashion. To determine whether PPARgamma ligands reduce this inflammation in part by reducing TH1 chemoattractant levels in vivo, the TZD pioglitazone was tested for its effects on a TH1 chemokine (CXCL10) in 2 models of colitis (i.e., dextran sodium sulfate and 2,4,6-dinitrobenzene sulfonic acid-mediated colitis). In both models, CXCL10 levels were significantly reduced by pioglitazone. Because TZDs can affect gene expression either directly, by regulating the binding of PPARgamma to consensus promoter elements, or indirectly, by modulating other signaling pathways that can affect gene transcription, the regulation of CXCL10 by TZDs was investigated in vitro in both HT-29 colon epithelial cells and THP-1 monocyte/macrophage cells. TZDs significantly reduced CXCL10 protein levels from activated HT-29 cells and THP-1-derived macrophages in a dose-dependent manner at nanomolar concentrations. However, TZDs did not affect messenger RNA levels or nuclear factor-kappaB activation at these concentrations in these cells. These findings imply the existence of a novel posttranscriptional regulatory antiinflammatory mechanism by TZDs that is not associated with reductions in nuclear factor-kappaB activation.
克罗恩病与过度的1型辅助性T（TH1）炎性免疫反应相关。减少与疾病相关的CD4 + TH1细胞流入发炎的肠道，可能有助于预防疾病发作，甚至可能减轻急性疾病的影响。噻唑烷二酮（TZD）配体可激活过氧化物酶体增殖物激活受体γ（PPARγ），在结肠炎小鼠模型中已显示其可减轻TH1炎症，主要是以预防方式。为了确定PPARγ配体是否部分通过降低体内TH1趋化因子水平来减轻这种炎症，在两种结肠炎模型（即葡聚糖硫酸钠和2,4,6 - 二硝基苯磺酸介导的结肠炎）中测试了TZD吡格列酮对TH1趋化因子（CXCL10）的影响。在这两种模型中，吡格列酮均显著降低了CXCL10水平。由于TZD可通过调节PPARγ与共有启动子元件的结合直接影响基因表达，或通过调节其他可影响基因转录的信号通路间接影响基因表达，因此在体外对HT - 29结肠上皮细胞和THP - 1单核细胞/巨噬细胞中TZD对CXCL10的调节进行了研究。TZD在纳摩尔浓度下以剂量依赖方式显著降低了活化的HT - 29细胞和THP - 1衍生巨噬细胞中的CXCL10蛋白水平。然而，在这些细胞的这些浓度下，TZD并未影响信使RNA水平或核因子κB的激活。这些发现表明存在一种由TZD介导的新型转录后调节抗炎机制，该机制与核因子κB激活的降低无关。
