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Deletion of IκBα activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A.

Abstract：

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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Neuhöfer P,Liang S,Einwächter H,Schwerdtfeger C,Wartmann T,Treiber M,Zhang H,Schulz HU,Dlubatz K,Lesina M,Diakopoulos KN,Wörmann S,Halangk W,Witt H,Schmid RM,Algül H

doi

10.1053/j.gastro.2012.09.058

subject

Has Abstract

pub_date

2013-01-01 00:00:00

pages

192-201

issue

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(12)01459-X

journal_volume

144

pub_type

杂志文章

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Deletion of IκBα activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A.