Parenchymal regression in chronic pancreatitis spares islets reprogrammed for the expression of NFkappaB and IAPs.
In advanced chronic pancreatitis (CP), islets are preserved even in the midst of scarring. We recently showed in CP local production of interferon (IFN)gamma, transforming growth factor (TGF)beta and death receptor ligand TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), along with functional death receptor neoexpression and apoptosis in exocrine but not in endocrine cells. However, islets are strongly induced for TRAIL-receptor (R)-4 lacking the functional death domain. TRAIL-R4 signaling in T cells induces NFkappaB, which activates antiapoptotic programs. Here, we demonstrate that in insulinoma cells CM, TGFbeta/IFNgamma/TRAIL in combination induced TRAIL-R4 surface expression. TRAIL/IFNgamma upregulated NFkappaB subunits and its target gene survivin while downmodulating IkappaB alpha mRNA. RelA transcriptional activity increased upon stimulation with IFNgamma and IFNgamma/TRAIL. In situ, normal pancreatic epithelia had low mRNA levels of NFkappaB subunits. These were higher in parenchymal areas of CP with severe fibrosis and highest in islets. NFkappaB-regulated proteins IkappaB alpha, survivin and another apoptosis inhibitor, cIAP1, were found in corresponding sites, again at highest levels in islets surrounded by fibrosis. In conclusion, islets in CP not only evade immune attack by nonexposure of functional death receptors in the presence of TRAIL-R4 but also additionally neoexpress NFkappaB and its target genes, survivin and cIAP1, to protect themselves from apoptosis.
Hasel
Cornelia
C
Department of Pathology, University of Ulm, Ulm, Germany. peter.moeller@medizin.uni-ulm.de
Bhanot
Umesh K
UK
Heydrich
René
R
Sträter
Jörn
J
Möller
Peter
P
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004848:Epithelium / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis*; D007340:Insulinoma; D007371:Interferon-gamma / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology*; D021122:Protein Subunits / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; D051996:Transcription Factor RelA / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000502:physiology; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D021122:Protein Subunits; C498143:RELA protein, human; D018124:Receptors, Tumor Necrosis Factor; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C451501:TNFRSF10D protein, human; C505653:TNFSF10 protein, human; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051550:I-kappa B Kinase