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Protects Cerulein-Induced Acute Pancreatitis by Repressing NF-
B Activation1
* Department of Forensic Medicine, Wakayama Medical University, Wakayama, Japan;
Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
We explored the pathophysiological roles of IFN-
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-
, KC/CXCL1, MIP-2/CXCL2, cyclooxygenase-2 (COX-2), and IFN- in WT mice. In situ hybridization combined with immunofluorescence analyses demonstrated that infiltrating neutrophils expressed IFN- mRNA. Unexpectedly, IFN-–/– mice exhibited exacerbated cerulein-induced pancreatic injury, with enhanced neutrophil recruitment. Moreover, intrapancreatic gene expression of TNF-, KC/CXCL1, MIP-2/CXCL2, and COX-2 were significantly exaggerated in IFN-–/– mice, compared with WT mice. Cerulein activated NF-
B, an indispensable transcription factor for gene transcription of TNF-, 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-B p65. In comparison with WT mice, IFN-–/– mice exhibited exaggerated and prolonged NF-B activation, probably due to reduced acetylation of Stat1, a main signal transducer of IFN-, because acetylated Stat1 can inhibit NF-B activation. Indeed, IFN- acetylated Stat1 and reciprocally reduced NF-B activation and COX-2 expression in neutrophils. Finally, even when administered 4 h after the first cerulein injection, IFN- remarkably attenuated acute pancreatitis in both WT and IFN-–/– mice, with reduced NF-B activation and COX-2 expression. Thus, IFN- can have anti-inflammatory effects on acute pancreatitis by depressing the proinflammatory consequences of NF-B activation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants-in-Aids from the Ministry of Education, Culture, Science and Technology of the Japanese Government.
2 Address correspondence and reprint requests to Dr. Toshikazu Kondo, Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan. E-mail address: kondot{at}wakayama-med.ac.jp
3 Abbreviations used in this paper: COX-2, cyclooxygenase-2; WT, wild type; pAb, polyclonal Ab; MPO, myeloperoxidase; AcLys, acetyl lysine; ISH, in situ hybridization; ChIP, chromatin immunoprecipitation.
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