Article
Lab Invest 2003, 83:825–836
In Chronic Pancreatitis, Widespread Emergence of TRAIL Receptors in Epithelia Coincides with Neoexpression of TRAIL by Pancreatic Stellate Cells of Early Fibrotic Areas
Supported by grants SFB518/A13 (to PM) and SFB518/A6 (to BR) from the Deutsche Forschungsgemeinschaft. HW was supported by the BioFuture Program of the BMF.
Cornelia Hasel1, Susanne Dürr1, Bettina Rau2, Jörn Sträter1, Roland M Schmid3, Henning Walczak5, Max G Bachem4 and Peter Möller1
- 1Department of Pathology, University of Ulm, Ulm, Germany
- 2Department of General Surgery, University of Ulm, Ulm, Germany
- 3Department of Medicine I, University of Ulm, Ulm, Germany
- 4Department of Clinical Chemistry and Pathobiochemistry, University of Ulm, Ulm, Germany
- 5the Deutsches Krebsforschungszentrum, Heidelberg, Germany
Correspondence: Dr. Peter Möller, Department of Pathology, University of Ulm, Albert-Einstein Allee 11, D-89081 Ulm, Germany. E-mail: peter.moeller@medizin.uni-ulm.de
Received 18 March 2003.
Abstract
TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis by cross-linking of the two TRAIL receptors that contain a death domain, TRAIL-R1 and TRAIL-R2. TRAIL-R3 and TRAIL-R4 are receptors that do not transmit an apoptotic signal. Our aim was to determine the expression of TRAIL and its receptors in normal pancreas and chronic pancreatitis. We applied real-time PCR, immunohisto(cyto)chemistry, and nick-end labeling of apoptoses. In normal pancreas, a minor subset of acinar cells coexpressed TRAIL-R2 and TRAIL-R4, whereas ductular epithelium and interstitial fibroblast-like cells (FLC) expressed TRAIL-R4. TRAIL-R1 and TRAIL-R3 were not detected in normal pancreas. In chronic pancreatitis, the exocrine epithelium strongly expressed TRAIL-R1, -R2, -R4, and, to a lesser extent, TRAIL-R3. Islets focally neoexpressed TRAIL-R1 and -R2 and intensely expressed TRAIL-R4. Changes in TRAIL receptor expression were most pronounced in areas of inflammatory infiltration and active fibrosis. In normal pancreas, expression of TRAIL was low on the mRNA level and undetectable on the protein level. In chronic pancreatitis, FLC in areas of active fibrosis expressed TRAIL. In addition, apoptoses were most numerous in these areas. We show that these FLC are pancreatic stellate cells. Pancreatic stellate cells express TRAIL in vivo and in vitro, and TRAIL expression is enhanced by IFN-
. Our findings indicate that the TRAIL/TRAIL receptor system is likely to be involved in chronic pancreatitis and suggest that pancreatic stellate cells may directly contribute to acinar regression by inducing apoptosis of parenchymal cells in a TRAIL-dependent manner.
