title: Pancreatitis-associated protein 2 modulates inflammatory responses in macrophages.
abstract: 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-alpha, and IL-10; no significant change was observed in IL-12, IL-15, and IL-18 when compared with controls. Chemical inhibition of the NFkappaB pathway abolished cytokine production and PAP facilitated nuclear translocation of NF-kappaB and phosphorylation of IkappaB alpha 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.
authors.affiliation: Department of Surgery, Downstate Medical Center, State University of New York, Brooklyn, NY 11203, USA.
authors.forename: Domenico
authors.initials: D
authors.lastname: Viterbo
authors.forename: Martin H
authors.initials: MH
authors.lastname: Bluth
authors.forename: Yin-Yao
authors.initials: YY
authors.lastname: Lin
authors.forename: Cathy M
authors.initials: CM
authors.lastname: Mueller
authors.forename: Raj
authors.initials: R
authors.lastname: Wadgaonkar
authors.forename: Michael E
authors.initials: ME
authors.lastname: Zenilman
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D017077:Culture Media, Conditioned; D016207:Cytokines; D037181:Lectins, C-Type; D016328:NF-kappa B; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; C000612146:Reg3a protein, rat; C000612144:Reg3b protein, rat