Activation of Nuclear Factor-kappa B in Acinar Cells Increases the Severity of Pancreatitis in Mice

作者：Huang Haojie; Liu Yan; Daniluk Jaroslaw; Gaiser Sebastian; Chu Jun; Wang Huamin; Li Zhao Shen; Logsdon Craig D; Ji Baoan^*

来源：Gastroenterology, 2013, 144(1): 202-210.

DOI：10.1053/j.gastro.2012.09.059

• Immune Regulation
• Cytokines
• RelA
• Gene Regulation

BACKGROUND %26 AIMS: Nuclear factor-kappa B (NF-kappa B) 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-kappa B protects against pancreatitis, and, in other cases, that it promotes this disease. We compared the effects of NF-kappa B in different mouse models of pancreatitis to understand these complications. METHODS: To model constitutive activation of NF-kappa B, we expressed a transgene that encodes its p65 subunit or the inhibitor of kappa B kinase (IKK) 2 in pancreatic acinar cells of mice. We analyzed effects on pancreatic tissues and levels of NF-kappa B target genes in these mice and compared them with mice that did not express transgenic p65 or IKK2 (controls). RESULTS: Transgenic expression of p65 led to compensatory expression of the inhibitory subunit IKB-alpha and, therefore, no clear phenotype. However, p65 transgenic mice given injections of cerulein, to induce acute pancreatitis, had higher levels of NF-kappa B 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-kappa B 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. CONCLUSIONS: The level of NF-kappa B 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-kappa B might be used to treat patients with acute or chronic pancreatitis.

• 出版日期2013-1
• 单位中国人民解放军第二军医大学