Early NF-kappaB activation is associated with hormone-induced pancreatitis.

Abstract

Inflammation and cell death are critical to pathogenesis of acute pancreatitis. Here we show that transcription factor nuclear factor-kappaB (NF-kappaB), which regulates these processes, is activated and plays a role in rat cerulein pancreatitis. NF-kappaB was strongly activated in the pancreas within 30 min of cerulein infusion; a second phase of NF-kappaB activation was prominent at 3-6 h. This biphasic kinetics could result from observed transient degradation of the inhibitory protein IkappaBalpha and slower but sustained degradation of IkappaBbeta. The hormone also caused NF-kappaB translocation and IkappaB degradation in vitro in dispersed pancreatic acini. Both p65/p50 and p50/p50, but not c-Rel, NF-kappaB complexes were manifest in pancreatitis and in isolated acini. Coinfusion of CCK JMV-180, which abolishes pancreatitis, prevented cerulein-induced NF-kappaB activation. The second but not early phase of NF-kappaB activation was inhibited by a neutralizing tumor necrosis factor-alpha antibody. Antioxidant N-acetylcysteine (NAC) blocked NF-kappaB activation and significantly improved parameters of pancreatitis. In particular, NAC inhibited intrapancreatic trypsin activation and mRNA expression of cytokines interleukin-6 and KC, which were dramatically induced by cerulein. The results suggest that NF-kappaB activation is an important early event that may contribute to inflammatory and cell death responses in acute pancreatitis.

• Authors: I Gukovsky, A S Gukovskaya, T A Blinman, V Zaninovic, S J Pandol
• Journal: The American journal of physiology (Am J Physiol) Vol. 275 Issue 6 Pg. G1402-14 (12 1998) ISSN: 0002-9513 [Print] United States
• PMID: 9843778 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Chemokines
• Cytokines
• DNA-Binding Proteins
• I-kappa B Proteins
• Interleukin-6
• NF-kappa B
• Tumor Necrosis Factor-alpha
• JMV 180
• keratinocyte-derived chemokines
• Ceruletide
• Sincalide
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Ceruletide (pharmacology)
• Chemokines
• Cytokines (genetics)
• DNA-Binding Proteins (metabolism)
• Gene Expression Regulation (drug effects, physiology)
• I-kappa B Proteins
• Interleukin-6 (genetics)
• Isomerism
• Kinetics
• Male
• NF-kappa B (antagonists & inhibitors, metabolism, physiology)
• Pancreas (drug effects)
• Pancreatitis (chemically induced, metabolism)
• Rats
• Rats, Sprague-Dawley
• Sincalide (analogs & derivatives, pharmacology)
• Tumor Necrosis Factor-alpha (physiology)