IFN-gamma protects cerulein-induced acute pancreatitis by repressing NF-kappa B activation.
We explored the pathophysiological roles of IFN-gamma in cerulein-induced acute pancreatitis. In wild-type (WT) mice, cerulein injection caused acute pancreatitis as evidenced by increased serum amylase levels and pathological changes such as interstitial edema, vacuolization, acinar cell necrosis, and neutrophil infiltration in pancreas. Concomitantly, cerulein treatment augmented intrapancreatic gene expression of TNF-alpha, KC/CXCL1, MIP-2/CXCL2, cyclooxygenase-2 (COX-2), and IFN-gamma in WT mice. In situ hybridization combined with immunofluorescence analyses demonstrated that infiltrating neutrophils expressed IFN-gamma mRNA. Unexpectedly, IFN-gamma(-/-) mice exhibited exacerbated cerulein-induced pancreatic injury, with enhanced neutrophil recruitment. Moreover, intrapancreatic gene expression of TNF-alpha, KC/CXCL1, MIP-2/CXCL2, and COX-2 were significantly exaggerated in IFN-gamma(-/-) mice, compared with WT mice. Cerulein activated NF-kappaB, an indispensable transcription factor for gene transcription of TNF-alpha, KC/CXCL1, MIP-2/CXCL2, and COX-2, in pancreas of cerulein-treated WT mice as evidenced by the increases in nuclear amount and DNA-binding activity of NF-kappaB p65. In comparison with WT mice, IFN-gamma(-/-) mice exhibited exaggerated and prolonged NF-kappaB activation, probably due to reduced acetylation of Stat1, a main signal transducer of IFN-gamma, because acetylated Stat1 can inhibit NF-kappaB activation. Indeed, IFN-gamma acetylated Stat1 and reciprocally reduced NF-kappaB activation and COX-2 expression in neutrophils. Finally, even when administered 4 h after the first cerulein injection, IFN-gamma remarkably attenuated acute pancreatitis in both WT and IFN-gamma(-/-) mice, with reduced NF-kappaB activation and COX-2 expression. Thus, IFN-gamma can have anti-inflammatory effects on acute pancreatitis by depressing the proinflammatory consequences of NF-kappaB activation.
Hayashi
Takahito
T
Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan.
Ishida
Yuko
Y
Kimura
Akihiko
A
Iwakura
Yoichiro
Y
Mukaida
Naofumi
N
Kondo
Toshikazu
T
D000208:Acute Disease; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D002108:Ceruletide / Q000008:administration & dosage* / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000378:metabolism / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000008:administration & dosage / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000276:Adjuvants, Immunologic; D052246:Cyclooxygenase 2 Inhibitors; D016328:NF-kappa B; D012333:RNA, Messenger; D012097:Repressor Proteins; D007371:Interferon-gamma; D002108:Ceruletide; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2