15-deoxyprostaglandin-j2 and Pancreatitis

The prostaglandin D2 metabolite, 15d-PGJ2, a potent natural ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), exerts antiinflammatory effects by inhibiting the induction of inflammatory response genes and NF-kappaB-dependent transcription. AIM To determine whether 15d-PGJ2 decreases the severity of secretagogue-induced acute pancreatitis (AP) and to assess cellular mechanisms contributing to these effects. METHODOLOGY Swiss Webster mice were injected with either saline or cerulein (50 microg/kg) hourly for 8 hours and received either 15d-PGJ2 (2 mg/kg) or vehicle 1 hour before and 4 hours after induction of AP. RESULTS Treatment with 15d-PGJ2 significantly attenuated AP, as determined by histologic assessment of edema, vacuolization, inflammation, and necrosis. This attenuation was associated with decreased cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1) expression and decreased serum and pancreatic IL-6 levels. Treatment with 15d-PGJ2 markedly inhibited NF-kappaB DNA-binding activity, and, moreover, this decreased activity was associated with a concomitant inhibition of IkappaB protein degradation. CONCLUSION Our findings demonstrate that 15d-PGJ2 attenuates the severity of AP most likely through the inhibition of COX-2 expression, IL-6 production, and NF-kappaB activation. Ligands specific for PPARgamma may represent novel and effective means of clinical therapy for AP.

Topics: Acute Disease; Animals; Blotting, Western; Cell Nucleus; Ceruletide; Cyclooxygenase 2; Electrophoretic Mobility Shift Assay; Female; Gene Expression Regulation; I-kappa B Proteins; Intercellular Adhesion Molecule-1; Interleukin-6; Isoenzymes; Ligands; Mice; NF-kappa B; Pancreatitis; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Protein Transport; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Time Factors; Transcription Factors