title: COX-2 inhibition results in alterations in nuclear factor (NF)-kappaB activation but not cytokine production in acute pancreatitis.
abstract: Acute pancreatitis is characterized by local inflammation and cytokine production, and release is thought to contribute to this process. Nuclear factor (NF)-kappaB activation and cytokine production are linked and inhibition of NF-kappaB has been shown to decrease the severity of pancreatitis. We have shown that inhibition of COX-2 ameliorates pancreatitis; however, the mechanism by which this effect occurs is unclear. Swiss Webster mice were injected intraperitoneally with either saline (control) or caerulein (CAE; 50 mg/kg) hourly for 8 hours; mice receiving CAE were further subdivided to receive saline or the cyclooxygenase-2 (COX-2) selective inhibitor (SC-58125; 10 mg, intraperitoneally) at the time of the first injection of CAE. Pancreata were harvested, histologic sections were scored, and protein was extracted to determine cytokine (interleukin [IL]-6, IL-1beta) levels and NF-kappaB subunits by ELISA and NF-kappaB activation by gel shift. In addition, serum was collected for measurement of cytokines. COX-2 inhibition resulted in decreased inflammation and a decrease in NF-kappaB activation. IL-6 and IL-1beta levels after COX-2 inhibition, however, remained elevated to levels equivalent to those of mice with histologic inflammation after CAE alone. COX-2 inhibition decreases inflammation as well as late-phase NF-kappaB activation but does not diminish levels of inflammatory cytokines, thus suggesting a two-phase activator of NF-kappaB. The attenuation of inflammation, despite unaltered cytokine levels, suggests that cytokines may not be critical for the inflammatory phase of pancreatitis.
authors.affiliation: Department of Surgery, The University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Michele I
authors.initials: MI
authors.lastname: Slogoff
authors.forename: Richard T
authors.initials: RT
authors.lastname: Ethridge
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Rajaraman
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
mesh_terms: D000208:Acute Disease; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D007375:Interleukin-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D010195:Pancreatitis / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D016328:NF-kappa B; D011720:Pyrazoles; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases