The PPARγ ligand, 15d-PGJ2, attenuates the severity of cerulein-induced acute pancreatitis

Introduction: The prostaglandin D-2 metabolite, 15d-PGJ(2), 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-PGJ(2) 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 mug/kg) hourly for 8 hours and received either 15d-PGJ(2) (2 mg/kg) or vehicle 1 hour before and 4 hours after induction of AP. Results: Treatment with 15d-PGJ(2) 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-PGJ(2) 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-PGJ(2) 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.