Department of Internal Medicine I, Regensburg University Medical Center, Germany.
Inflamm Bowel Dis. 2010 Nov;16(11):1850-8. doi: 10.1002/ibd.21294.
A disturbed regulation of Toll-like receptor (TLR) signal transduction resulting in the exclusive activation of proinflammatory signaling pathways may be critical for the perpetuation of established chronic colitis. Glycogen synthase kinase 3-β (GSK3-β) was recently identified as an important regulator of TLR signaling mediating excessive inflammatory responses. The aim of this study was to assess the role of GSK3-β activity in chronic intestinal inflammation.
Chronic colitis was induced by dextran sodium sulfate (DSS) treatment. Mice were treated intraperitoneally with phosphate-buffered saline (PBS), CpG-ODN, or GSK3-β inhibitors (SB216763, LiCl). Intestinal inflammation was evaluated by histologic analysis and cytokine secretion of mesenteric lymph node cells (MLC). Nuclear extracts of MLC and lamina propria mononuclear cells (LPMC) were analyzed for nuclear factor kappaB (NF-κB) and CREB activity. Murine and human intestinal immune cells were stimulated in vitro with CpG-ODN, lipopolysaccharide (LPS), or anti-CD3 with or without LiCl.
GSK3-β blockade significantly reduced chronic intestinal inflammation and even abolished the colitis-intensifying effects of CpG-ODN treatment. In vitro inhibition of GSK3-β reduced the proinflammatory phenotype of both murine and human intestinal immune cells from chronic inflamed tissue. In vivo blockade of GSK3-β resulted in a shift from NF-κB activity toward CREB activity in murine MLC and LPMC.
Blockade of GSK3-β attenuates excessive proinflammatory TLR-mediated immune responses. GSK3-β inhibition therefore constitutes a promising therapeutic option for selectively reducing exaggerated intestinal immune reactions toward the luminal flora in inflammatory bowel disease.
Toll 样受体（TLR）信号转导的失调导致促炎信号通路的特异性激活，可能对已建立的慢性结肠炎的持续存在至关重要。糖原合成酶激酶 3-β（GSK3-β）最近被确定为 TLR 信号转导的重要调节剂，介导过度的炎症反应。本研究旨在评估 GSK3-β 活性在慢性肠道炎症中的作用。
通过葡聚糖硫酸钠（DSS）处理诱导慢性结肠炎。用磷酸盐缓冲盐水（PBS）、CpG-ODN 或 GSK3-β 抑制剂（SB216763、LiCl）对小鼠进行腹腔内治疗。通过组织学分析和肠系膜淋巴结细胞（MLC）的细胞因子分泌评估肠道炎症。分析 MLC 和固有层单核细胞（LPMC）的核提取物中的核因子 kappaB（NF-κB）和 CREB 活性。用 CpG-ODN、脂多糖（LPS）或抗-CD3 在有或没有 LiCl 的情况下体外刺激鼠和人肠道免疫细胞。
GSK3-β 阻断显著减轻慢性肠道炎症，甚至消除 CpG-ODN 治疗的结肠炎加重作用。体外抑制 GSK3-β 降低了来自慢性炎症组织的鼠和人肠道免疫细胞的促炎表型。体内阻断 GSK3-β导致鼠 MLC 和 LPMC 中的 NF-κB 活性向 CREB 活性转移。
抑制 GSK3-β 可减轻过度的 TLR 介导的促炎免疫反应。因此，GSK3-β 抑制构成了一种有前途的治疗选择，可选择性地减少炎症性肠病中对腔内腔菌群的过度肠道免疫反应。
