II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität Munich, Munich, Germany.
Gastroenterology. 2013 Jan;144(1):192-201. doi: 10.1053/j.gastro.2012.09.058. Epub 2012 Oct 3.
BACKGROUND & AIMS: The transcription factor nuclear factor-κB (NF-κB) (a heterodimer of NF-κB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-κB promotes or protects against AP. We used the NF-κB inhibitor protein, inhibitor of κB (IκB)α, to study the roles of NF-κB in the development of AP in mice.
IκBα or the combination of IκBα and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L-arginine were used to induce AP. We performed microarray analyses of the IκBα- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin.
Mice with pancreas-specific deletion of IκBα had constitutive activation of RelA and a gene expression profile consistent with NF-κB activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of IκBα and RelA. By using genome-wide expression analysis, we identified a cluster of NF-κB-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IκBα-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis.
Pancreas-specific deletion of IκBα results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP.
转录因子核因子-κB（NF-κB）（NF-κB1p50 和 RelA 的异二聚体）在急性胰腺炎（AP）中迅速激活。然而，NF-κB 是否促进或保护 AP 尚不清楚。我们使用 NF-κB 抑制剂蛋白 IκBα 来研究 NF-κB 在小鼠 AP 发展中的作用。
使用 Cre/lox 交叉 P 策略从小鼠胰腺中选择性缺失 IκBα 或 IκBα 和 RelA 的组合；使用 cerulein 或 L-精氨酸诱导 AP。我们对 IκBα 和 RelA 缺失的胰腺进行了微阵列分析。分析了来自健康个体和急性或慢性胰腺炎患者的编码区中α-1-抗胰蛋白酶的变体。
具有胰腺特异性 IκBα 缺失的小鼠中 RelA 持续激活，基因表达谱与 NF-κB 激活一致；这些小鼠的 AP 发展减弱，胰蛋白酶激活受损。然而，在胰腺特异性缺失 IκBα 和 RelA 的小鼠中完全诱导了 AP。通过使用全基因组表达分析，我们鉴定了一组可能保护 AP 发展的 NF-κB 调节基因。丝氨酸蛋白酶抑制剂 2A（Spi2a）在 IκBα 缺陷小鼠中高度上调。慢病毒介导的 Spi2A 表达降低了 C57BL/6 和 RelA 缺陷小鼠中 AP 的发展。然而，我们没有将任何与 Spi2a 同源的α-1-抗胰蛋白酶的变体与急性或慢性胰腺炎相关联。
胰腺特异性 IκBα 的缺失导致 RelA 的核易位，并减少了 cerulein 或 L-精氨酸给药后小鼠的 AP 诱导和胰蛋白酶激活。RelA 的组成性激活上调 Spi2A，从而保护小鼠免受 AP 的发展。
