Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice.
Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice.
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DOI：
10.1053/j.gastro.2012.09.059
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发表时间：
2013-01
期刊：
影响因子：
29.4
通讯作者：
Ji B
中科院分区：
文献类型：
--
作者：
Huang H;Liu Y;Daniluk J;Gaiser S;Chu J;Wang H;Li ZS;Logsdon CD;Ji B
核因子（NF）-κB在胰腺炎的早期阶段被激活。这种转录因子调节控制许多细胞活动的基因，包括炎症和存活。有证据表明，NF-κB的激活可以预防胰腺炎，在其他情况下，它可以促进胰腺炎。我们比较了NF-κB在不同胰腺炎小鼠模型中的作用，以了解这些并发症。为了模拟NF-κB的组成性激活，我们在小鼠胰腺腺泡细胞中表达了编码其p65亚基或κB激酶抑制剂（IKK）2的转基因。我们分析了这些小鼠胰腺组织和NF-κB靶基因水平的影响，并将其与不表达转基因p65或IKK 2的小鼠（对照组）进行了比较。p65的转基因表达导致抑制性亚基IKB-α的补偿性表达，因此没有明确的表型。然而，注射雨蛙肽诱导急性胰腺炎的p65转基因小鼠的腺泡细胞中NF-κB活性水平更高，炎症水平更高，结果比对照小鼠更严重。相反，IKK 2的组成性表达直接增加腺泡细胞中NF-κB的活性并诱导胰腺炎。IKK 2活性延长（3个月）导致星状细胞活化、腺泡细胞丢失和纤维化，这是慢性胰腺炎的特征。与对照组相比，IKK 2和p65的共表达大大增加了炎症介质的表达和胰腺炎的严重程度。NF-κB活化水平与急性胰腺炎的严重程度相关。较长时间的激活（3个月）导致慢性胰腺炎。这些发现表明，抑制NF-κB的策略可用于治疗急性或慢性胰腺炎患者。
Nuclear factor (NF)-κB is activated during early stages of pancreatitis. This transcription factor regulates genes that control many cell activities, including inflammation and survival. There is evidence that activation of NF-κB protects against pancreatitis, and in other cases, that it promotes this disease. We compared the effects NF-κB in different mouse models of pancreatitis to understand these complications. To model constitutive activation of NF-κB, we expressed a transgene that encodes its p65 subunit or the inhibitor of κB kinase (IKK) 2 in pancreatic acinar cells of mice. We analyzed effects on pancreatic tissues and levels of NF-κB target genes in these mice and compared them to mice that did not express transgenic p65 or IKK2 (controls). Transgenic expression of p65 led to compensatory expression of the inhibitory subunit IKB-α and therefore, no clear phenotype. However, p65 transgenic mice given injections of caerulein, to induce acute pancreatitis, had higher levels of NF-κB activity in acinar cells, greater levels of inflammation, and more severe outcomes than control mice. In contrast, constitutive expression of IKK2 directly increased the activity of NF-κB in acinar cells and induced pancreatitis. Prolonged activity of IKK2 (3 months) resulted in activation of stellate cells, loss of acinar cells, and fibrosis, which are characteristics of chronic pancreatitis. Co-expression of IKK2 and p65 greatly increased the expression of inflammatory mediators and the severity of pancreatitis, compared with control mice. The level of NF-κB activation correlates with the severity of acute pancreatitis in mice. Longer periods of activation (3 months) lead to chronic pancreatitis. These findings indicate that strategies to inactivate NF-κB might be used to treat patients with acute or chronic pancreatitis.
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