The PPARgamma ligand, 15d-PGJ2, attenuates the severity of cerulein-induced acute 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.
Hashimoto
Koji
K
Department of Surgery, The University of Texas Medical Branch, Galveston, Texas 77555-0536, USA.
Ethridge
Richard T
RT
Saito
Hiroshi
H
Rajaraman
Srinivasan
S
Evers
B Mark
BM
D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002108:Ceruletide / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood; D007527:Isoenzymes / Q000378:metabolism; D008024:Ligands; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
C477819:15-deoxyprostaglandin J2; D020672:I-kappa B Proteins; D015850:Interleukin-6; D007527:Isoenzymes; D008024:Ligands; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1; D002108:Ceruletide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015230:Prostaglandin D2