Interleukin-18, Together with Interleukin-12, Induces Severe Acute Pancreatitis in Obese but Not in Nonobese Leptin-Deficient Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-06, Vol.105 (23), p.8085-8090
• Main Authors: Sennello, Joseph A., Fayad, Raja, Pini, Maria, Gove, Melissa E., Ponemone, Venkatesh, Cabay, Robert J., Siegmund, Britta, Dinarello, Charles A., Fantuzzi, Giamila
• Format: Article
• Language: English
• Subjects: Acute Disease; Acute-Phase Reaction; Adipose Tissue - drug effects; Adipose Tissue - pathology; Adipose tissues; Alcoholic pancreatitis; Amylases - blood; Animals; Apoptosis; Biological Sciences; Calcium; Calcium - blood; Cytokines; Disease Susceptibility; Female; Gangrene; Gene Expression Regulation - drug effects; Inflammation; Interferon-gamma - blood; Interleukin-12 - pharmacology; Interleukin-18 - pharmacology; Interleukin-6 - blood; Leptin - administration & dosage; Leptin - deficiency; Leptin - pharmacology; Lipase - blood; Lithostathine - genetics; Lithostathine - metabolism; Mice; Mice, Obese; Necrosis; Obesity; Obesity - complications; Pancreas; Pancreatitis; Pancreatitis - chemically induced; Pancreatitis - complications; Pancreatitis - pathology; Pancreatitis-Associated Proteins; Proteins - genetics; Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Time Factors; Tissues
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0804091105

Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short- and long-term leptin replacement therapy. Short-term leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.