Selective inhibition of NF-kappaB attenuates the severity of cerulein-induced acute pancreatitis.
BACKGROUND
Acute pancreatitis (AP) is associated with increased cytokine production, which can ultimately produce deleterious local and systemic effects. The transcription factor NF-kappaB is activated by degradation of its inhibitory factor, IkappaB, and can stimulate various cytokines. The purpose of this study was to determine whether the inhibition of NF-kappaB binding activity with a novel peptide that binds to the NF-kappaB essential modifier binding domain (NBD) could attenuate the severity of AP.


METHODS
AP was induced in Swiss Webster mice by hourly injections of the cholecystokinin analogue cerulein (50 microg/kg). Mice were injected with either the wild-type or control (mutated) NBD peptide at the time of the first cerulein injection; they were then sacrificed over a time course, and pancreata and lungs were harvested for histologic analysis and scoring. Myeloperoxidase activity was measured to assess neutrophil sequestration as an indicator of inflammation. NF-kappaB binding activity and steady-state levels of IkappaB and NF-kappaB subunits were determined by gel shift and Western blot, respectively.


RESULTS
AP resulted in increased NF-kappaB DNA-binding activity and decreased steady-state levels of IkappaB. Treatment with NBD peptide decreased inflammation in the pancreas, decreased hemorrhage in the lungs, and decreased myeloperoxidase activity in both pancreas and lung.


CONCLUSIONS
The marked induction of NF-kappaB binding activity suggests a role for this transcription factor in the early inflammatory changes associated with AP. Treatment with the NBD peptide attenuated the severity of injury associated with AP. Novel compounds that selectively target NF-kappaB may prove to be useful treatment of AP and AP-associated lung injury.
Ethridge
Richard T
RT
Departments of Surgery, The University of Texas Medical Branch, Galveston 77555-0533, USA.
Hashimoto
Koji
K
Chung
Dai H
DH
Ehlers
Richard A
RA
Rajaraman
Srinivasan
S
Evers
B Mark
BM
D000208:Acute Disease; D000818:Animals; D002108:Ceruletide; D002766:Cholecystokinin / Q000031:analogs & derivatives; D004247:DNA / Q000378:metabolism; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010455:Peptides; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding
D020672:I-kappa B Proteins; C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; D002108:Ceruletide; D004247:DNA; D002766:Cholecystokinin; D009195:Peroxidase