| First Author | Neuhöfer P | Year | 2013 |
| Journal | Gastroenterology | Volume | 144 |
| Issue | 1 | Pages | 192-201 |
| PubMed ID | 23041330 | Mgi Jnum | J:257245 |
| Mgi Id | MGI:6119103 | Doi | 10.1053/j.gastro.2012.09.058 |
| Citation | Neuhofer P, et al. (2013) Deletion of IkappaBalpha activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology 144(1):192-201 |
| abstractText | BACKGROUND & AIMS: The transcription factor nuclear factor-kappaB (NF-kappaB) (a heterodimer of NF-kappaB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-kappaB promotes or protects against AP. We used the NF-kappaB inhibitor protein, inhibitor of kappaB (IkappaB)alpha, to study the roles of NF-kappaB in the development of AP in mice. METHODS: IkappaBalpha or the combination of IkappaBalpha 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 IkappaBalpha- 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 IkappaBalpha had constitutive activation of RelA and a gene expression profile consistent with NF-kappaB 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 IkappaBalpha and RelA. By using genome-wide expression analysis, we identified a cluster of NF-kappaB-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IkappaBalpha-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 IkappaBalpha 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. |
