COX-2 inhibition results in alterations in nuclear factor (NF)-kappaB activation but not cytokine production in acute pancreatitis.
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.
Slogoff
Michele I
MI
Department of Surgery, The University of Texas Medical Branch, Galveston, Texas 77555, USA.
Ethridge
Richard T
RT
Rajaraman
Srinivasan
S
Evers
B Mark
BM
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*
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