Early NF-kappaB activation is associated with hormone-induced pancreatitis.
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.
Gukovsky
I
I
Department of Medicine, Veterans Affairs Medical Center, West Los Angeles and University of California, Los Angeles, California 90073, USA.
Gukovskaya
A S
AS
Blinman
T A
TA
Zaninovic
V
V
Pandol
S J
SJ
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002108:Ceruletide / Q000494:pharmacology; D018925:Chemokines; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000235:genetics; D007536:Isomerism; D007700:Kinetics; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D010179:Pancreas / Q000187:drug effects; D010195:Pancreatitis / Q000139:chemically induced* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012844:Sincalide / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000975:Antioxidants; D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C058451:JMV 180; C074302:keratinocyte-derived chemokines; D002108:Ceruletide; D012844:Sincalide; D000111:Acetylcysteine