Inhibition of myeloid differentiation 1 specifically in colon with antisense oligonucleotide exacerbates dextran sodium sulfate-induced colitis
Inhibition of myeloid differentiation 1 specifically in colon with antisense oligonucleotide exacerbates dextran sodium sulfate-induced colitis
复制标题
用反义寡核苷酸抑制结肠中的骨髓分化1会加剧右旋糖酐硫酸钠诱导的结肠炎
DOI：
10.1002/jcb.28947
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发表时间：
2019-10-01
影响因子：
4
通讯作者：
Peng, Zhiyong
中科院分区：
文献类型：
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作者：
Chen, Xiaoxing;Pan, Huaqin;Peng, Zhiyong
髓样分化1（MD-1），也称为淋巴细胞抗原86（Ly 86），是与MD-2同源的可溶性蛋白，并与辐射防护105（RP 105）形成复合物。RP 105/MD-1复合物负调节Toll样受体4（TLR 4）信号传导，并参与多种免疫疾病。然而，MD-1在炎症性肠病（IBD）中的确切作用仍然知之甚少。为了进一步研究MD-1在IBD中的参与，我们用反义寡核苷酸（AS-ODN）抑制结肠中的MD-1，并评估MD-1抑制对葡聚糖硫酸钠（DSS）诱导的结肠炎的影响。我们发现MD-1蛋白表达在溃疡性结肠炎患者和DSS诱导的结肠炎小鼠中均显著降低。我们首次发现，小鼠口服MD-1 AS-ODN可显著抑制结肠而非全身组织中MD-1蛋白水平。随后，我们发现MD-1 AS-ODN处理的小鼠更容易受到DSS诱导的结肠炎的影响，这是基于体重减轻、结肠长度、组织学评分和疾病活动指数。MD-1抑制还显著增强结肠中炎性细胞因子如IL-6和IL-1 β的产生。最后，与对照组相比，用MD-1 AS-ODN处理的小鼠在DSS暴露后表现出TLR 4和MyD 88的信使RNA水平增加，并且表现出增强的核因子（NF）-κ B活化。总之，AS-ODN特异性抑制结肠组织中MD-1的表达可加重DSS诱导的小鼠实验性结肠炎，这可能与激活TLR 4/NF-κ B信号通路有关。
Myeloid differentiation 1 (MD-1), also known as lymphocyte antigen 86 (Ly86), is a soluble protein homologous to MD-2 and forms a complex with radioprotective 105 (RP105). RP105/MD-1 complex negatively regulates toll-like receptor 4 (TLR4) signaling and is involved in several immune disorders. However, the precise role of MD-1 in inflammatory bowel diseases (IBD) remains poorly understood. To further investigate the involvement of MD-1 in IBD, we inhibited MD-1 in colon with antisense oligonucleotide (AS-ODN) and assessed the effect of MD-1 inhibition on dextran sodium sulfate (DSS)-induced colitis. We discovered that MD-1 protein expression was remarkably decreased in both patients with ulcerative colitis and mice with DSS-induced colitis. For the first time, we showed that oral administration of MD-1 AS-ODN to mice significantly suppressed the MD-1 protein levels in colon rather than systemic tissues. Subsequently, we found that MD-1 AS-ODN treated mice were more susceptible to DSS-induced colitis based on loss of body weight, colon length, histological scores, and disease activity index. MD-1 inhibition also significantly enhanced inflammatory cytokines production such as IL-6 and IL-1 beta in colons. Finally, mice treated with MD-1 AS-ODN exhibited increased messenger RNA levels of TLR4 and MyD88 after DSS exposure and showed enhanced nuclear factor (NF)-kappa B activation compared with the control. Taken together, specifically suppression of MD-1 in colon tissues with AS-ODN exacerbates DSS-induced experimental colitis in mice, which is possibly related to activation of TLR4/NF-kappa B signaling.