Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Early NF-kappaB activation is associated with hormone-induced pancreatitis. 984 78

The eukaryotic transcription factor NF-kappaB/Rel is activated by a large variety of stimuli. We have recently shown that NF-kappaB/Rel is induced during the course of caerulein pancreatitis. Here, we show that activation of NF-kappaB/Rel by caerulein, a CCK analog, requires increasing intracellular Ca2+ levels and protein kinase C activation. Caerulein induces a dose-dependent increase of nuclear NF-kappaB/Rel binding activity in pancreatic lobules, which is paralleled by degradation of IkappaBalpha. IkappaBbeta was only slightly affected by caerulein treatment. Consistent with an involvement of Ca2+, the endoplasmic reticulum-resident Ca2+-ATPase inhibitor thapsigargin activated NF-kappaB/Rel in pancreatic lobules. The intracellular Ca2+ chelator TMB-8 prevented IkappaBalpha degradation and subsequent nuclear translocation of NF-kappaB/Rel induced by caerulein. BAPTA-AM was less effective. Cyclosporin A, a Ca2+/calmodulin-dependent protein phosphatase (PP2B) inhibitor, decreased caerulein-induced NF-kappaB/Rel activation and IkappaBalpha degradation. The inhibitory effect of bisindolylmaleimide suggests that protein kinase C activity is also required for caerulein-induced NF-kappaB/Rel activation. These data suggest that Ca2+- as well as protein kinase C-dependent mechanisms are required for caerulein-induced NF-kappaB/Rel activation.
 ...
PMID:Caerulein-induced NF-kappaB/Rel activation requires both Ca2+ and protein kinase C as messengers. 1048 94

The eukaryotic transcription factor nuclear factor-kappaB (NF-kappaB)/Rel is activated by a large variety of stimuli. It has been demonstrated that NF-kappaB/Rel is induced during the course of cerulein pancreatitis. Here, we show that NF-kappaB/Rel is differentially activated in pancreatic lobules. Cerulein induces NF-kappaB/Rel via activation of IkappaB kinase (IKK), which causes degradation of IkappaBalpha but not IkappaBbeta. Tumor necrosis factor-alpha-mediated IKK activation leads to IkappaBalpha and IkappaBbeta degradation. In contrast, oxidative stress induced by H(2)O(2) activates NF-kappaB/Rel independent of IKK activation and IkappaBalpha degradation; instead IkappaBalpha is phosphorylated on tyrosine. H(2)O(2) but not cerulein-mediated NF-kappaB/Rel activation can be blocked by stabilizing microtubules with Taxol. Inhibition of tubulin polymerization with nocodazole causes NF-kappaB/Rel activation in pancreatic lobules. These results propose three different pathways of NF-kappaB/Rel activation in pancreatic acinar cells. Furthermore, these data demonstrate that microtubules play a key role in IKK-independent NF-kappaB/Rel activation following oxidative stress.
 ...
PMID:Different modes of NF-kappaB/Rel activation in pancreatic lobules. 1212 73

Reactive oxygen species (ROS) has been considered to be an important regulator in the development and pathogenesis of pancreatitis and an activator of the transcription factor, nuclear factor-kappaB (NF-kappaB), regulating inflammatory cytokine gene expression. NF-kappaB activation was demonstrated in cerulein pancreatitis, which rapidly induces an acute, edematous form of pancreatitis. This study aimed to investigate whether cerulein induced ROS generation, lipid peroxide and hydrogen peroxide production, NF-kappaB activation, and expression of cytokines (IL-1beta, IL-6) in pancreatic acinar cells. An additional aim was to establish whether these alterations were inhibited by antioxidants such as glutathione, superoxide dismutase, and catalase and an inhibitor of NF-kappaB activation, pyrrolidine dithiocarbamate (PDTC). To determine the possible interactions of the antioxidants and PDTC with cerulein-induced signaling, Ca2+ signal and amylase release were monitored in the pancreatic acinar cells treated with cerulein in the presence or absence of either the antioxidants or PDTC. The results showed that cerulein generated ROS and increased lipid peroxide and hydrogen peroxide production in the acinar cells, as determined by dichlorofluorescein diacetate dye. This resulted in NF-kappaB activation and the induction of cytokine gene expression in the cells. The cerulein-induced NF-kappaB activation was in parallel to IkappaBalpha degradation. Cerulein also induced Ca2+ signals and amylase release in acinar cells. Both antioxidants (glutathione, superoxide dismutase, catalase) and PDTC inhibited the cerulein-induced, oxidant-mediated alterations but did not affect the cerulein-evoked Ca2+ signals and amylase release in acinar cells. In conclusion, ROS, generated by cerulein, activates NF-kappaB, resulting in the up-regulation of inflammatory cytokine gene expression in acinar cells. NF-kappaB inhibition by scavenging ROS might alleviate the inflammatory response in pancreatic acinar cells by suppressing cytokine gene expression.
 ...
PMID:Suppression of cerulein-induced cytokine expression by antioxidants in pancreatic acinar cells. 1237 70

Nuclear factor (NF)-kappaB plays a central role in acute pancreatitis. We studied cerulein (CER)-induced pancreatitis in NF-kappaB knockout (KO) mice. NF-kappaB KO mice and normal control littermate wild-type (WT) mice were given four hyperstimulating doses of cerulein every hour to elicit secreatagogue-induced pancreatitis. Malonildialdehyde activity, glutathione levels, myeloperoxidase activity, TNF-alpha, and NF-kappaB binding activity and its inhibitory protein IkappaBalpha were studied in the pancreas. Furthermore, we measured plasma lipase and amylase and the histological damage. KO mice had reduced malonildialdehyde levels (WT + CER = 4.083 +/- 0.95 micromol/g; KO + CER = 1.513 +/- 0.63 microol/g), decreased myeloperoxidase activity (WT + CER = 19.3 +/- 2.39 mU/g; KO + CER = 10.21 +/- 2.05 mU/g), increased glutathione levels (WT + CER 6.22 +/- 2.46 micromol/g; KO + CER = 15. 516 +/- 2.92 micromol/g), and reduced serum levels of amylase (WT + CER = 2519 +/- 656.9 U/L; KO + CER = 916 +/- 280.4 U/L) and lipase (WT + CER = 1420 +/- 170 U/L; KO + CER = 861 +/- 172. 3 U/L). KO mice showed reduced pancreatic NF-kappaB activation, decreased TNF-alpha tissue content, and reduced histologic alterations. Our data suggest that KO mice have an attenuated cerulein-induced pancreatitis and help to define the possible interaction between NF-kappaB activation and oxidative stress in this deleterious event.
 ...
PMID:Attenuated cerulein-induced pancreatitis in nuclear factor-kappaB-deficient mice. 1469 Dec 90

The cholecystokine (CCK) analogue cerulein causes pathophysiological, morphological, and biochemical events similar to various aspects of human pancreatitis. Doses of CCK or cerulein beyond those that cause the maximum pancreatic secretion of amylase and lipase result in pancreatitis, which is characterized by a dysregulation of the digestive enzyme production and cytoplasmic vacuolization and the death of acinar cells, edema formation, and an infiltration of inflammatory cells into the pancreas. This study aims to investigate whether cerulein induces IL-8 expression in pancreatic acinar cells, and whether cerulein-induced IL-8 expression is inhibited in the cells transfected with mutant genes for c-jun (TAM-67), or IkappaBalpha (MAD-3) or treated inhibitors of mitogen-activated protein kinases (MAPKs). As a result, cerulein induced IL-expression, which was inhibited in the cells transfected with TAM-67 or MAD-3 or treated inhibitors of MAPK. In conclusion, activation of MAPK, nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1) may be the upstream signaling for cerulein-induced IL-8 expression in pancreatic acinar cells.
 ...
PMID:Role of mitogen-activated protein kinases, NF-kappaB, and AP-1 on cerulein-induced IL-8 expression in pancreatic acinar cells. 1738 81

Angiotensin II is a key mediator of inflammation, and nuclear factor-kappaB (NF-kappaB) plays a critical role in various inflammatory diseases, including acute pancreatitis (AP). This study sought to elucidate the mechanism mediating angiotensin II involvement in angiotensin II type 1 (AT1) receptor-mediated NF-kappaB activation, and ultimately in proinflammatory actions of AP pathogenesis. A rat model of obstructive pancreatitis was induced by ligation of the common biliopancreatic duct. Pancreatic injury was determined by assessing pancreatic histology, myeloperoxidase activity, and serum interleukin-6. Protein levels of pancreatic angiotensinogen and AT1 receptor as well as NF-kappaB inhibitory subunits (IkappaBalpha and IkappaBbeta) and phospho-NF-kappaB p65, kappaB-related proteins (intercellular adhesion molecule-1, cyclooxygenase-2, and interleukin-1), and NADPH oxidase isoforms p67 and p22 were examined by Western blot. Nuclear kappaB binding activity and degree of oxidative stress were determined by electrophoretic mobility shift assay and glutathione/nitrotyrosine examination, respectively. The effects of losartan, an AT1 receptor antagonist, on NF-kappaB-mediated proinflammatory actions were also assessed. Induction of AP was associated with a time-dependent increase in pancreatic angiotensinogen levels. AT1 receptor blockade with losartan improved the pancreatic histological damage, myeloperoxidase activity, and serum interleukin-6. Losartan treatment also reduced AP-associated depletion of IkappaBbeta and elevation of phospho-NF-kappaB p65 protein expression as well as the enhanced nuclear kappaB binding activity and elevated levels of kappaB-related proteins. In addition, losartan treatment suppressed pancreatic glutathione and nitrotyrosine levels, which were consistent with decreased NADPH oxidase expression. These data provide substantial evidence that angiotensin II is involved in AT1 receptor-mediated NADPH oxidase-dependent NF-kappaB activation; thus, it might ultimately promote proinflammatory actions during AP pathogenesis.
 ...
PMID:Angiotensin II type 1 receptor-dependent nuclear factor-kappaB activation-mediated proinflammatory actions in a rat model of obstructive acute pancreatitis. 1761 60

Heat shock proteins (HSPs), induced by a variety of stresses, are known to protect against cellular injury. Recent studies have demonstrated that prior beta-adrenergic stimulation as well as thermal or culture stress induces HSP70 expression and protects against cerulein-induced pancreatitis. The goal of our current studies was to determine whether or not a non-thermal, chemical stressor like sodium arsenite also upregulates HSP70 expression in the pancreas and prevents secretagogue-induced trypsinogen and NF-kappaB activation. We examined the effects of sodium arsenite preadministration on the parameters of cerulein-induced pancreatitis in rats and then monitored the effects of preincubating pancreatic acini with sodium arsenite in vitro. Our results showed that sodium arsenite pretreatment induced HSP70 expression both in vitro and in vivo and significantly ameliorated the severity of cerulein-induced pancreatitis, as evidenced by the markedly reduced degree of hyperamylasemia, pancreatic edema, and acinar cell necrosis. Sodium arsenite pretreatment not only inhibited trypsinogen activation and the subcellular redistribution of cathepsin B, but also prevented NF-kappaB translocation to the nucleus by inhibiting the IkappaBalpha degradation both in vivo and in vitro. We also examined the effect of sodium arsenite pretreatment in a more severe model of pancreatitis induced by L-arginine and found a similarly protective effect. Based on our observations we conclude that, like thermal stress, chemical stressors such as sodium arsenite also induce HSP70 expression in the pancreas and protect against acute pancreatitis. Thus, non-thermal pharmacologically induced stress can help prevent or treat pancreatitis.
 ...
PMID:Sodium arsenite induces heat shock protein 70 expression and protects against secretagogue-induced trypsinogen and NF-kappaB activation. 1794 Oct 83