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J. Biol. Chem., Vol. 279, Issue 8, 7199-7207, February 20, 2004

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p8 Improves Pancreatic Response to Acute Pancreatitis by Enhancing the Expression of the Anti-inflammatory Protein Pancreatitis-associated Protein I^*

Sophie Vasseur, Emma Folch-Puy, Verena Hlouschek¶, Stephane Garcia||, Fritz Fiedler**, Markus M. Lerch, Jean Charles Dagorn, Daniel Closa¶¶, and Juan Lucio Iovanna||||

From the Centre de Recherche INSERM, EMI 0116, 163 Avenue de Luminy, BP172, 13009 Marseille, France, the ^¶Medizinische Klinik B, Westfälische Wilhelms-Universität, 48129 Müster, Germany, the ^||Hôpital Nord, Chemin des Bourrellys, 13915 Marseille, France, the ^**Institut für Anästhesie, Klinikum Mannheim, Theodor-Kutzer-Ufer, D-68167, Mannheim, Germany, the Division of Gastroenterology and Endocrinology, Department of Medicine A, Ernst-Moritz-Arndt Universität Greifswald, Friedrich-Löffler-Str. 23A, 17487 Greifswald, Germany, and the Department of Experimental Pathology, IIBB-CSIC, c/Rossello 161, 7°, 08036 Barcelona, Spain

p8 is a transcription cofactor whose expression is strongly and rapidly activated in pancreatic acinar cells during the acute phase of pancreatitis. A p8-deficient mouse strain was generated as a tool to investigate its function. Upon induction of acute pancreatitis, myeloperoxidase activity in pancreas and serum concentrations of amylase and lipase were much higher and pancreatic lesions more severe in p8-deficient mice than in wild-type, indicating that p8 expression decreased pancreatic sensitivity to pancreatitis induction. The protective mechanism might involve the pancreatitis-associated protein (PAP I), whose strong induction during pancreatitis is p8-dependent, because administration of anti-PAP I antibodies to rats increased pancreatic inflammation during pancreatitis. In addition, 100 ng/ml PAP I in the culture medium of macrophages prevented their activation by tumor necrosis factor , strongly suggesting that PAP I was an anti-inflammatory factor. Finally, PAP I was able to inhibit NFB activation by tumor necrosis factor , in macrophages and in the AR42J pancreatic acinar cell line. In conclusion, p8 improves pancreatic resistance to inducers of acute pancreatitis by a mechanism implicating the expression of the anti-inflammatory protein PAP I.

Received for publication, August 18, 2003 , and in revised form, November 7, 2003.

^* This work was supported by grants from Association pour le Recherche sur le Cancer and Ligue Contre le Cancer (to J. L. I.) and Fonds de Investigaciones Sanitories PI020286 (to D. C.). 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.

Both authors contributed equally to this work.

^¶¶ To whom correspondence may be addressed: Dept. of Experimental Pathology, IIBB-CSIC, c/Rossello 161, 7°, 08036 Barcelona, Spain. Tel.: 34-93-3638307; Fax: 34-93-3638301; E-mail: dcabam{at}iibb.csic.es.

^|||| To whom correspondence may be addressed: Centre de Recherche INSERM, EMI 0116, 163 Avenue de Luminy, BP172, F-13009 Marseille, France. Tel.: 33-491-827533; Fax: 33-491-826083; E-mail: iovanna{at}marseille.inserm.fr.

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