[Parenchymal regression in chronic pancreatitis spares islets reprogrammed for expression of NFkappaB and IAPs].
In chronic pancreatitis (CP), fibrous replacement of exocrine tissue spares islets. There is local production of IFNgamma and death ligands by inflammatory cells as well as TGFbeta and TRAIL by pancreatic stellate cells (PSCs), along with functional death receptor neo-expression and apoptosis in exocrine but not in endocrine cells. Moreover, islets are strongly induced for TRAIL-receptor(R)-4 lacking a functional death domain. TRAIL-R4 signalling in T-cells induces NFkappaB transcription factors which activate anti-apoptotic programs. Whether TRAIL elicits this response in endocrine cells, we tested human insulinoma cell line CM and determined NFkappaB subunits transcripts and NFkappaB dependent inhibitor of apoptosis proteins (IAPs) in normal pancreas (NP) and CP. We treated CM with cytokines, determined TRAIL-R expression by flow cytometry, graded degree of fibrosis in CP specimens, microdissected epithelial compartments, performed real time PCRs for NFkappaB subunits transcripts, and immunohistochemistry for IKK-gamma, IkappaB-alpha, RelA, survivin, and cIAP1. In CM, TGFbeta/IFNgamma/TRAIL induced TRAIL-R4 surface expression. TRAIL/ IFNgamma, upregulated NFkappaB subunits and survivin while down-modulating 1kappaBalpha. NP epithelia had low RNA levels of NFkappaB subunits. These were increased in parenchymal areas of CP with severe fibrosis and most intensely in islets. The NFkappaB regulated proteins IkappaBalpha, survivin, and cIAP1 were found in corresponding sites, again, at highest levels in islets surrounded by fibrosis. In CP, islets not only evade immune attack by non-exposure of functional death receptors in presence of TRAIL-R4. They also neo-express NFkappaB subunits, survivin, and cIAP1. This apoptosis-inhibitory security program might be enforced by PSC-derived TRAIL.
Hasel
Cornelia
C
Institut für Pathologie, Universität Ulm.
Bhanot
Umesh K
UK
Maier
René
R
Sträter
Jörn
J
Möller
Peter
P
D002908:Chronic Disease; D004847:Epithelial Cells / Q000166:cytology / Q000473:pathology; D005786:Gene Expression Regulation; D007426:Genes, Intracisternal A-Particle / Q000235:genetics*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics*; D010195:Pancreatitis / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human