¹Department of Pathology, University of Ulm, Ulm, Germany

Correspondence: Dr P Möller, MD, Department of Pathology, University of Ulm, Albert-Einstein-Allee 11, Ulm D-89081, Germany. E-mail: peter.moeller@medizin.uni-ulm.de

^*These authors contributed equally to this work.

Received 13 April 2005; Revised 31 May 2005; Accepted 2 June 2005; Published online 22 August 2005.

Abstract

In advanced chronic pancreatitis (CP), islets are preserved even in the midst of scarring. We recently showed in CP local production of interferon (IFN), transforming growth factor (TGF) 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 NFB, which activates antiapoptotic programs. Here, we demonstrate that in insulinoma cells CM, TGF/IFN/TRAIL in combination induced TRAIL-R4 surface expression. TRAIL/IFN upregulated NFB subunits and its target gene survivin while downmodulating IB mRNA. RelA transcriptional activity increased upon stimulation with IFN and IFN/TRAIL. In situ, normal pancreatic epithelia had low mRNA levels of NFB subunits. These were higher in parenchymal areas of CP with severe fibrosis and highest in islets. NFB-regulated proteins IB, 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 NFB and its target genes, survivin and cIAP1, to protect themselves from apoptosis.