Pancreatitis-associated protein I suppresses NF-kappa B activation through a JAK/STAT-mediated mechanism in epithelial cells.
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-kappaB 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-kappaB inhibition, pointing to a cross-talk between JAK/STAT3 and NF-kappaB signaling pathways. Together, these findings indicate that PAP I inhibits the inflammatory response by blocking NF-kappaB 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.
Folch-Puy
Emma
E
Department of Experimental Pathology, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Cientificas, c/Rosselló 161 7o, 08036 Barcelona, Spain.
Granell
Susana
S
Dagorn
Jean C
JC
Iovanna
Juan L
JL
Closa
Daniel
D
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D019000:Phosphotyrosine / Q000378:metabolism; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D016328:NF-kappa B; D000073718:Pancreatitis-Associated Proteins; D047428:Protein Kinase Inhibitors; C000612141:REG3A protein, human; D012333:RNA, Messenger; C000612142:Reg2 protein, rat; C000612144:Reg3b protein, rat; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D016753:Interleukin-10; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases