Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice

Haojie Huang, Yan Liu, Jaroslaw Daniluk, Sebastian Gaiser, Jun Chu, Huamin Wang, Zhao Shen Li, Craig D. Logsdon, Baoan D Ji

Research output: Contribution to journalArticle

105 Citations (Scopus)

Abstract

Background & Aims: Nuclear factor-κB (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 of NF-κB in different mouse models of pancreatitis to understand these complications. Methods: 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 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- and, therefore, no clear phenotype. However, p65 transgenic mice given injections of cerulein, 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)202-210
Number of pages9
JournalGastroenterology
Volume144
Issue number1
DOIs
StatePublished - Jan 2013

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Acinar Cells
Pancreatitis
Chronic Pancreatitis
I-kappa B Kinase
Inflammation
Ceruletide
Transgenes
Transgenic Mice
Genes
Fibrosis
Transcription Factors
Phenotype
Injections

Keywords

  • Cytokines
  • Gene Regulation
  • Immune Regulation
  • RelA

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice. / Huang, Haojie; Liu, Yan; Daniluk, Jaroslaw; Gaiser, Sebastian; Chu, Jun; Wang, Huamin; Li, Zhao Shen; Logsdon, Craig D.; Ji, Baoan D.

In: Gastroenterology, Vol. 144, No. 1, 01.2013, p. 202-210.

Research output: Contribution to journalArticle

Huang, H, Liu, Y, Daniluk, J, Gaiser, S, Chu, J, Wang, H, Li, ZS, Logsdon, CD & Ji, BD 2013, 'Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice', Gastroenterology, vol. 144, no. 1, pp. 202-210. https://doi.org/10.1053/j.gastro.2012.09.059
Huang, Haojie ; Liu, Yan ; Daniluk, Jaroslaw ; Gaiser, Sebastian ; Chu, Jun ; Wang, Huamin ; Li, Zhao Shen ; Logsdon, Craig D. ; Ji, Baoan D. / Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice. In: Gastroenterology. 2013 ; Vol. 144, No. 1. pp. 202-210.
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AU - Huang, Haojie

AU - Liu, Yan

AU - Daniluk, Jaroslaw

AU - Gaiser, Sebastian

AU - Chu, Jun

AU - Wang, Huamin

AU - Li, Zhao Shen

AU - Logsdon, Craig D.

AU - Ji, Baoan D

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N2 - Background & Aims: Nuclear factor-κB (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 of NF-κB in different mouse models of pancreatitis to understand these complications. Methods: 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 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- and, therefore, no clear phenotype. However, p65 transgenic mice given injections of cerulein, 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. Conclusions: 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.

AB - Background & Aims: Nuclear factor-κB (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 of NF-κB in different mouse models of pancreatitis to understand these complications. Methods: 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 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- and, therefore, no clear phenotype. However, p65 transgenic mice given injections of cerulein, 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. Conclusions: 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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