Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice.
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.
Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
Joseph A
JA
Sennello
Raja
R
Fayad
Maria
M
Pini
Melissa E
ME
Gove
Venkatesh
V
Ponemone
Robert J
RJ
Cabay
Britta
B
Siegmund
Charles A
CA
Dinarello
Giamila
G
Fantuzzi
D000208:Acute Disease; D000210:Acute-Phase Reaction; D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000681:Amylases / Q000097:blood; D000818:Animals; D002118:Calcium / Q000097:blood; D004198:Disease Susceptibility; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000494:pharmacology*; D020382:Interleukin-18 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood; D020738:Leptin / Q000008:administration & dosage / Q000172:deficiency* / Q000494:pharmacology; D008049:Lipase / Q000097:blood; D051847:Lithostathine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D009336:Necrosis; D009765:Obesity / Q000150:complications*; D010195:Pancreatitis / Q000139:chemically induced* / Q000150:complications* / Q000473:pathology; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D020382:Interleukin-18; D015850:Interleukin-6; D020738:Leptin; D051847:Lithostathine; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C000612141:REG3A protein, human; D012333:RNA, Messenger; C497615:Reg1 protein, mouse; C490253:Reg3b protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma; D008049:Lipase; D000681:Amylases; D002118:Calcium