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Pancreatitis-Associated Protein 2 Modulates Inflammatory Responses in Macrophages¹

Department of Surgery, Downstate Medical Center, State University of New York, Brooklyn, NY 11203

Pancreatitis-associated proteins (PAP) are stress-induced secretory proteins that are implicated in immunoregulation. Previous studies have demonstrated that PAP is up-regulated in acute pancreatitis and that gene knockdown of PAP correlated with worsening severity of pancreatitis, suggesting a protective effect for PAP. In the present study, we investigated the effect of PAP2 in the regulation of macrophage physiology. rPAP2 administration to clonal (NR8383) and primary macrophages were followed by an assessment of cell morphology, inflammatory cytokine expression, and studies of cell-signaling pathways. NR8383 macrophages which were cultured in the presence of PAP2 aggregated and exhibited increased expression of IL-1, IL-6, TNF-, and IL-10; no significant change was observed in IL-12, IL-15, and IL-18 when compared with controls. Chemical inhibition of the NFB pathway abolished cytokine production and PAP facilitated nuclear translocation of NF-B and phosphorylation of IB inhibitory protein suggesting that PAP2 signaling involves this pathway. Cytokine responses were dose dependent. Interestingly, similar findings were observed with primary macrophages derived from lung, peritoneum, and blood but not spleen. Furthermore, PAP2 activity was inhibited by the presence of serum, inhibition which was overcome with increased PAP2. Our results demonstrate a new function for PAP2: it stimulates macrophage activity and likely modulates the inflammatory environment of pancreatitis.

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 Data were presented in part at the Joint Meeting of the American Pancreatic Association/International Association of Pancreatology, November 1–4, 2006, Chicago, IL and at Digestive Disease Week, the 107th Annual Meeting of the Gastroenterological Association, May 20–25, 2006, Los Angeles, CA by D. Viterbo, Y. Y. Lin, C. M. Mueller, M. E. Zenilman, and M. H. Bluth.

² Address correspondence and reprint requests to Dr. Martin H. Bluth at the current address: Wayne State University School of Medicine, 8203 Scott Hall, 540 East Canfield Avenue, Detroit, MI 48201. E-mail address: mbluth{at}med.wayne.edu

³ Abbreviations used in this paper: PAP, pancreatitis-associated protein; Ct, cycle threshold.

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The JI 2008 181: 1593-1594. [Full Text]  

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