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Pancreatitis-Associated Protein I Suppresses NF-B Activation through a JAK/STAT-Mediated Mechanism in Epithelial Cells¹

Emma Folch-Puy^*, Susana Granell^*, Jean C. Dagorn, Juan L. Iovanna and Daniel Closa^2,*

^* Department of Experimental Pathology, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Cientificas, Barcelona, Spain; and Centre de Recherche, Institut National de la Santé et de la Recherche Médicale, Unité 624, Stress Cellulaire, Marseille, France

Pancreatitis-associated protein I (PAP I), also known as HIP, p23, or Reg2 protein, has recently been implicated in the endogenous regulation of inflammation. Although it was initially characterized as a protein that is overexpressed in acute pancreatitis, PAP I has also been associated with a number of inflammatory diseases, such as Crohn’s disease. Knowing that PAP I and IL-10 responses share several features, we have used a pancreatic acinar cell line (AR42J) to assess the extent to which their expression is reciprocally regulated, and whether the JAK/STAT and NF-B signaling pathways are involved in the suppression of inflammation mediated by PAP I. We observed that PAP I is induced in epithelial cells by IL-10 and by PAP I itself. In contrast, we found phosphorylation and nuclear translocation of STAT3 and induction of suppressor of cytokine signaling 3 in response to PAP I exposure. Finally, a JAK-specific inhibitor, tyrphostin AG490, markedly prevented PAP I-induced NF-B inhibition, pointing to a cross-talk between JAK/STAT3 and NF-B signaling pathways. Together, these findings indicate that PAP I inhibits the inflammatory response by blocking NF-B activation through a STAT3-dependent mechanism. Important functional similarities to the anti-inflammatory cytokine IL-10 suggest that PAP I could play a role similar to that of IL-10 in epithelial cells.

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